A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

Article abstract of DOI:10.1021/acs.joc.0c01897

The aza-Prins reaction is a widely employed and highly efficient method for the preparation of saturated nitrogen-containing heterocycles. Its major drawback has always been a lack of diastereoselectivity and the formation of racemic products. Herein, we address these problems and report, for the first time, the synthesis of both diastereomerically and enantiopure multiply substituted piperidines via the aza-Prins reaction. This method is widely applicable for natural product synthesis and is exemplified here by the synthesis of enantiopure pipecolic acid derivatives.

Full text of DOI:10.1021/acs.joc.0c01897

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Article
A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure
Piperidines and Pipecolic Acids
Ramana Reddy Mittapalli, Simon J. Coles, Wim T. Klooster, and Adrian P. Dobbs*
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ABSTRACT: The aza-Prins reaction is a widely employed and highly efficient method for the preparation of saturated nitrogen-
containing heterocycles. Its major drawback has always been a lack of diastereoselectivity and the formation of racemic products.
Herein, we address these problems and report, for the first time, the synthesis of both diastereomerically and enantiopure multiply
substituted piperidines via the aza-Prins reaction. This method is widely applicable for natural product synthesis and is exemplified
here by the synthesis of enantiopure pipecolic acid derivatives.
with both relative and absolute stereocontrol of the
substituents.
INTRODUCTION
■
Nitrogen heterocycles are among the most important
structural component in both natural products and modern
pharmaceuticals.1 For example, 2,6-disubstituted and 2,4,6-
trisubstituted piperidines are found widely in alkaloids.
Analysis of all FDA approved drugs show that 59% of
small molecule drugs contain a nitrogen heterocycle and that
72 drugs contain a piperidine moiety, making it the most
prevalent nitrogen heterocycle in approved drugs (Figure
1a).1 The two most common substitution patterns are N- and
Since it was first reported by Hanschke in 1955, the Prins
cyclization has become one of the leading methods for the
preparation of tetrahydropyran rings.6 For many years, this
remained a highly diastereoselective but racemic reaction. A
limited number of asymmetric cyclization processes to give
enantiopure tetrahydropyrans have been reported, either
commencing from enantiopure starting materials7−9 or
employing an asymmetric catalyst approach.10−13 More
recently, the aza-Prins14−21 (and related aza-silyl-Prins22−25
)
cyclizationthe reaction of a homoallylic amine and
aldehyde (or acetal or epoxide) promoted by a Lewis or
Brønsted acid (Scheme 1)has emerged as a highly efficient
method for the diastereoselective synthesis of substituted
piperidines, albeit in racemic form. While methods for the
asymmetric synthesis of heterocycles via chiral iminium ion
cyclizations have been extensively reviewed,26 there are only
isolated examples of attempts at simple asymmetric aza-Prins
reactions. There remains no general catalytic and asymmetric
aza-Prins cyclization reaction, and interest in developing
enantioselective aza-Prins processes is high and very
challenging. Recently, we reported a related asymmetric aza-
Figure 1. (a) Most abundant nitrogen heterocycles within FDA
approved drugs and their occurrence; (b) most popular positions of
piperidine substitution.1
C(4)-, followed by C(2)- and C(3) (Figure 1b). The vast
majority of these drugs require careful stereocontrol of the
substitutents around the ring during manufacture. Methods
for their synthesis have been widely reviewed,2−5 but the
greatest problem has always been the asymmetric con-
struction of the piperidine ring. Furthermore, there is an
emerging need for sp3-rich heterocyclic frameworks, again
Received: August 6, 2020
Published: January 8, 2021
https://dx.doi.org/10.1021/acs.joc.0c01897
© 2021 American Chemical Society
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when employing a chiral center adjacent to nitrogen in the
homoallylic amine starting material and thus generating a
new chiral center across the nitrogen after cyclization.
To test this hypothesis, starting from (R)-allyl glycine, it
was possible to prepare (R)-allylmorpholin-2-one (3) in a
single step. Attempting the aza-Prins reaction using FeCl3
and phenyl propionaldehyde afforded the corresponding
piperidine (4, Scheme 2) in 63% yield, with the expected
Scheme 1. (1) The aza-Prins Reactions, Giving a
Diastereomeric Mixture through Nonselective Trapping at
C-4, and (2) Rationale in Designing a Chiral Auxiliary to
Direct C-4 Trapping
Scheme 2. 2,6-trans-Selective aza-Prins Reaction Starting
from (R)-Allylmorpholin-2-one Generates an Equal
Mixture of Adducts at C-4
exclusive trans-relationship of substituents across the nitrogen,
but surprisingly with little selectivity at the C-4 position
compared with employing (1). We reasoned that the
introduction of either one or two substituents on the two
bridging carbons in (3) may improve the C-4 selectivity of
the aza-Prins reaction.
silyl-Prins reaction,27 and Maruoka described an aza-Prins
endo-type cyclization of 2-(1-phenylvinyl)benzaldehyde and
BocNH2 catalyzed by a BINOL-derived N-triflyl phosphor-
amide to form 1-aminoindenes.28
Herein, we report for the first time a highly novel, efficient,
and high yielding diastereo- and enantioselective aza-Prins
reaction, offering the ability to access enantiopure multi-
substituted sp3-rich piperidines.
Therefore, we prepared mono (8)32 and diphenyl (7)33,34
allylmorpholin-2-ones in both enantiomeric forms in just 4
steps, as two new chiral platforms containing a homoallylic
amine. Following the rationale presented in Scheme 1(2), the
phenyl substituents were chosen, as these would both
facilitate rapid removal of part of the chiral platform post
Prins cyclization and crucially block one face from anion
trapping. Treatment of either 7 or 8 with NaHMDS and an
allyl or propargylic bromide gave a small library of
enantiomerically pure secondary amines (Table 1).
RESULTS AND DISCUSSION
■
In designing an asymmetric aza-Prins reaction, we were
conscious that one of the considerable drawbacks of the aza-
Prins cyclization has been the necessity for an N-
sulfonamide14,15 group (Ts, Ns, Bs) in the homoallylic
amine component (1); groups such as N-benzyl or N-Boc do
not undergo aza-Prins cyclization.17,20,29 Further, we recently
reported that chiral auxiliaries on nitrogen, for example α-
methylbenzyl, in place of the tosyl group, were inefficient for
promoting asymmetric aza-silyl-Prins-type reactions.27 There-
fore, we instead focused on developing a novel and easy to
prepare and use chiral-auxiliary-containing homoallylic amine.
We previously showed that the aza-Prins and aza-silyl-Prins
reactions are 2,6-trans selective across the nitrogen17,23,27,30,31
and reasoned that this trans relationship would be maintained
We attempted aza-Prins reactions utilizing (7a) with a
range of aldehydes using Brønsted and Lewis acids to
promote the reaction. With TFA, the reaction of (7a) with
butanal proceeded smoothly at room temperature to afford
76% of an enantiomerically pure single diastereoisomer (9a)
with only traces of the opposite C-4 diastereomer being
isolated and which could easily be separated by chromatog-
raphy (Table 2, entry 1). Starting from the opposite
enantiomer (7b) gave the enantiomeric product (Table 2,
entry 2). The same result was observed with a number of
Table 1. Synthesis of Chiral Homoallylic Amines
a
entry
R1
R2
alkyl halide
allyl bromide
allyl bromide
propargyl bromide
crotyl bromide
R
product
% yield
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
CH2CHCH2
CH2CHCH2
CH2CCH
CH2CHCH(CH3)
CH2C(CH3) CH2
CH2CHC(CH3)2
7
81
85
85
86
90
80
8a
8b
8c
8d
8e
3-bromo-2-methylprop-1-ene
1-bromo-3-methylbut-2-ene
a
Isolated and purified yields. All products were isolated as a single enantiomer and diastereoisomer.
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enantiomer in every case (Table 2, entries 3−8). The
structure of (9g) was confirmed by X-ray crystallography and
also studied by 2D NMR and NOESY experiments. These
data were used to confirm the structural assignments for all
compounds (9a−g) as they gave almost identical 2D and
NOESY spectra to the spectra obtained for (9g) where X-ray
crystallography also confirmed the structure. The use of
glyoxylic acid gave a tricyclic product, whereby the acid
moiety had trapped the intermediate carbocation intra-
molecularly (Table 2, entry 9). Replacing TFA with pTSA
gave the -OTs trapped adduct but as an inseparable mixture
of diastereoisomers (Table 2, entry 10). Finally, acetals could
be employed in place of aldehydes and also gave high yields
of a single enantiomerically pure product (Table 2, entry 11).
In the absence of a suitable nucleophile, it is also known
that solvents such as acetonitrile or benzene can trap the
cyclic secondary carbocation, in an aza-Prins-Ritter or aza-
Prins-Friedel−Crafts cascade.21,36 Using pTSA in acetonitrile
gave good yields of the 4-NHAc trapped products (Table 3),
again as a single enantiomer and diastereomer.
Table 2. Asymmetric aza-Prins Reactions Employing
Brønsted Acids
Table 3. Asymmetric aza-Prins−Ritter Reactions
a
entry starting material
aldehyde
product % yield
1
2
3
4
5
6
7
8
9
7a
7b
7a
7a
7a
7a
7a
7a
7a
7a
3-phenylpropionaldehyde
3-phenylpropionaldehyde
octanal
decanal
hexanal
10a
10a′
10b
10c
10d
10e
10e
10f
83
76
73
78
75
74
65
82
63
78
butanal
butanal diethyl acetal
phenylacetaldehyde
styrene oxide
10f
10g
10
diphenylacetaldehyde
a
Isolated and purified yields. All products were isolated as a single
enantiomer and diastereoisomer.
In place of TFA or TsOH, the alternative is to use a Lewis
acid to promote the aza-Prins cyclization, with iron and
indium trihalides being particularly prevalent in the literature.
In these cases, the Lewis acid provides a nucleophile to trap
the secondary carbocation. When initially trialing Lewis acids,
a disappointing 62:38 ratio of diastereoisomers was obtained
when starting from (7b) and iron trichloride (Table 4, entry
1). Somewhat surprisingly, changing to the monophenyl
amine (8) gave much improved results and a single
diastereomer product in excellent yield. However, the
configuration of the halogen is the opposite to that observed
for the diphenyl starting materials (7a/7a′). Both iron
trichloride and iron tribromide gave excellent yields of 4-halo
products (12a−d, 13a, b), as long as the appropriate halide-
containing solvent was employed, to avoid mixed-halogen
products (Table 3). The structure of (12d) was confirmed by
X-ray crystallography and also by 2D NMR and NOESY
experiments. This combined knowledge was utilized to
confirm the structural assignments for compounds (11−
16b) as they gave almost identical 2D and NOESY spectra
a
b
Isolated and purified yields. All products were isolated as a single
c
enantiomer and diastereoisomer. Structure was confirmed by X-ray
crystallography.35 Using TsOH instead of TFA, giving an 65:35
d
inseparable mixture.
other aldehydes, all proceeding in excellent yields and
diastereoselectivities and giving the product as a single
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Table 4. Asymmetric aza-Prins Reactions Employing Lewis Acids
a
b
entry
R1
aldehyde
X
acid
product
% yield
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
3-phenylpropionaldehyde
3-phenylpropionaldehyde
benzaldehyde
diphenylacetaldehyde
butanal
3-phenylpropionaldehyde
diphenylacetaldehyde
butanal
dodecanal
butanal diethyl acetal
decanal
dodecanal
decanal
Cl
Cl
Cl
Cl
Cl
Br
Br
OH
OH
OH
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeBr3
FeBr3
TFA
TFA
TFA
PTSA
PTSA
BF3·OEt2
BF3·OEt2
11
67 (62:38)
12a
12b
12c
12d
13a
13b
14a
14b
14a
15a
15b
16a
90
91
89
c
89
90
80
88
90
76
80
78
9
10
11
12
13
14
OTs
OTs
NHAc
NHAc
d
75
d
dodecanal
16b
72
a
b
Other halogen containing Lewis acids (TiCl4, SnCl4, AlCl3) gave lower yields and decomposition of starting material. Isolated and purified yields.
All products were isolated as a single enantiomer and diastereoisomer (except entry 1). Structure was confirmed by X-ray crystallography.37
c
d
CH3CN was used as solvent.
around the ring hydrogens to the spectra obtained for (12d)
where X-ray crystallography had also confirmed the structure.
The methodology was then extended to incorporate other
nucleophiles into the monophenyl amine (8). Reaction of 8
with butanal in the presence of TFA (2 equiv) surprisingly
gave the hydroxy product (14a) in 88% yield (Table 4 entry
8). The same outcome was observed with other aldehydes
(Table 4 entry 8), and an acetal (Table 4 entry 10).
Replacing TFA with pTSA in DCM provided tosyl-
substituted derivatives in excellent yields (15a, b, Table 4,
entries 11 and 12). Finally, conducting the reaction in
acetonitrile and optimized with boron trifluoride etherate, a
sequential aza-Prins cyclization−Ritter reaction was observed,
giving single amine products in high yield and selectivity
(16a, b, Table 4 entries 13 and 14) but with the opposite
stereochemistry at C4 (cf 10a−h).
Substituted allyl and propargylic amines (Table 1) were the
next to be employed in the cyclization and furnished a range
of substituted products (Table 5). Using (3S,5S)-3-((E)-but-
2-enyl)-5-phenylmorpholin-2-one (8c, Table 5 entry 1) gave
very high yields of the methyl-substituted product as a single
diastereoisomer and enantiomer under either Lewis or
Brønsted acid conditions. When using (3S,5S)-3-(3-methyl-
but-2-enyl)-5-phenylmorpholin-2-one (8e, Table 5 entries 2−
4), the formation of a 5-membered ring was observed,
presumably via the more stable tertiary carbocation, and
irrespective of the aldehyde or acid employed.17 (3S,5S)-3-(2-
Methylallyl)-5-phenylmorpholin-2-one (8d, entries 5−8) gave
a new single isomer quaternary chiral center. Finally, using
(3S,5S)-5-phenyl-3-(prop-2-ynyl) morpholin-2-one (8b, entry
9) gave a single vinyl halide-containing diastereoisomer and
enantiomer where either Cl or Br could be incorporated into
the product. The structures of (17c) and (19b) were
additionally confirmed by X-ray crystallography in addition to
the 2D NMR and NOESY experiments used to assign all the
structures and stereochemistry in Table 5.
The morpholin-2-one was not considered as a chiral
auxiliary because part of it remains in the final product;
therefore, it is seen as a highly efficient chiral platform for
controlling the aza-Prins reaction. Partial removal of the
chiral platform was easily achieved via catalytic hydro-
genation, from both the mono- and diphenyl substituted
bicyclic compounds, to afford enantiopure pipecolic acid
derivatives. All substituents at the C4-position tolerated these
deprotection conditions except in vinyl halo compounds 20a
and 20b, where the halogen was lost along with the alkene
during hydrogenation (Table 6, entry 6). Use of acidified
ethanol as the solvent furnished the ethyl ester product.
CONCLUSIONS
■
In summary, we report a highly efficient asymmetric aza-Prins
reaction capable of furnishing enantiopure piperidines and
pipecolic acid derivatives in excellent yields and as a single
enantiomer and diastereomer. We believe that this method
will be of great use in total synthesis and the development of
novel 3D structures, exploring new chemical space, and we
shall report our findings in due course.
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Table 5. Asymmetric aza-Prins Reactions Employing
Substituted Alkenes or Alkynes
Table 6. Synthesis of Substituted Pipecolic Acids via
Partial Removal of the Chiral Platform
a
b
entry
R (starting material)
R1
X
% yield
c
1
2
3
4
5
6
(CH2)2CH3 (9a/9a′)
(CH2)6CH3 (9e)
(CH2)2Ph (10a/10a′)
(CH2)2CH3 (14a)
(CH2)2Ph (12a)
Ph
Ph
Ph
H
H
H
OH
OH
NHAc
OH
Cl
95/93 (21a)
92 (21b)
91/89 (21c/21c′)
76 (21d)
68 (21e)
51/57 (21f)
d
(CH2)2Ph (20a/20b)
H
a
Stereochemistry of X in starting material different depending on if
the monophenyl or diphenyl compound was used (Table 2, cf Table
4); stereochemical integrity of X from the starting material was
b
maintained in all products. Isolated and purified yields. All products
were isolated as a single enantiomer and diastereoisomer. Reaction
c
was performed on both enantiomers of starting material (93% for
d
(2S,4S,6R)-product and 95% for (2R,4R,6S)-product). Product was
isolated as the ethyl ester using acidified ethanol (EtOH-HCl).
using a hybrid quadrupole-orthogonal acceleration time-of-flight
system.
(R)-Methyl 2-(Benzylamino)pent-4-enoate. To a stirred
solution of (R)-methyl 2-aminopent-4-enoate (500 mg, 3.8 mmol,
1 equiv) and benzaldehyde (1.1 equiv) in MeOH (10 mL) was
added NaBH3CN (2 equiv) at 0 °C and brought to rt. After 12 h,
the reaction mixture was quenched with 1 mL of water and
concentrated to remove methanol. The organic layer was washed
with water and brine, dried over anhydrous MgSO4, filtered,
concentrated, and separated by column chromatography on silica gel
(eluted with EtOAc/hexanes, 1:5) to afford 800 mg (90%) as a
26
color less liquid. [α]D = +32.0 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3): δ 7.33−7.24 (m, 5H), 5.80−5.68 (m, 1 H), 5.17−
5.04 (m, 2 H), 3.88−3.63 (m, 5 H), 3.37 (t, J = 6.4 Hz, 1 H), 2.42
(t, J = 8.4 Hz, 2 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
175.1, 139.7, 133.6, 129.1, 128.4, 128.3, 127.1, 118.0, 77.4, 77.0,
76.7, 60.3, 52.0, 51.7, 37.7 ppm; νmax(neat)/cm−1: 3453, 2950, 1583,
1455, 1321, 1123, 762, 591 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C13H18NO2: 220.1337; found: 220.1332.
(R)-Methyl 2-(4-Methylphenylsulfonamido)pent-4-enoate.
To a stirred solution of (R)-methyl 2-aminopent-4-enoate (500
mg, 3.8 mmol, 1 equiv) in DCM (10 mL) was added Et3N (1
equiv) at 0 °C and TsCl was added following. After 12 h, the
reaction mixture was quenched with 1 mL of water. The organic
layer was washed with water and brine, dried over anhydrous
MgSO4, filtered, concentrated, and separated by column chromatog-
raphy on silica gel (eluted with EtOAc/hexanes, 1:5) to afford 910
mg (83%) as a color less liquid. [α]D = −50.0 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3): δ 7.71−7.68 (m, 2H), 7.28−7.24 (m, 2
H), 5.65−5.54 (m, 1 H), 5.25 (t, J = 9.2 Hz, 1 H), 5.09−5.02 (m, 2
H), 4.02−3.97 (m, 1 H), 3.49 (s, 3 H), 2.43 (t, J = 6.8 Hz, 1 H),
2.39 (s, 3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 171.4,
143.7, 136.9, 131.4, 129.9, 129.7, 127.5, 127.3, 127.0, 119.7, 55.3,
52.4, 37.6, 21.6 ppm; νmax(neat)/cm−1: 3466, 3013, 1596, 1421,
1335, 1067, 785, 585 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C13H18NO4S 284.0956; found 284.0950.
(R)-3-Allylmorpholin-2-one (3). To a stirred solution of (R)-2-
aminopent-4-enoic acid (500 mg, 3.8 mmol, 1 equiv) and
dibromoethane (1.0 equiv) in CH3CN (10 mL) was added
K2CO3 (2 equiv) at 0 °C and brought to reflux. After 12 h, the
reaction mixture was cooled to RT and concentrated to remove
CH3CN. The organic layer was washed with water and brine, dried
over anhydrous MgSO4, filtered, concentrated and separated by
a
b
Isolated and purified yields. All products were isolated as a single
c
enantiomer and diastereoisomer. Structure was confirmed by X-ray
crystallography.38
26
1
EXPERIMENTAL SECTION
■
General Methods. All dry solvents were prepared/dried
according to standard procedures. Reactions were performed in
oven-dried round-bottom flasks. The flasks were fitted with rubber
septa, and the reactions were conducted under nitrogen atmosphere.
Reaction mixtures were purified by flash column chromatography on
silica gel 100−200 mesh. TLC plates were visualized by exposure to
ultraviolet light and/or by exposure to acidic ethanolic solution of
ninhydrin followed by heating (<1 min) on a hot gun (∼250 °C).
Organic solutions were concentrated on a rotary evaporator at 35−
40 °C. H NMR and 13C NMR (proton-decoupled) spectra were
1
recorded on 400 and 500 MHz NMR spectrometers in DMSO−D6/
MeOD/CDCl3/D2O as solvent as indicated. Chemical shifts (δ)
were reported in parts per million (ppm) with respect to TMS as an
internal standard. Coupling constants (J) are quoted in hertz (Hz).
High resolution mass spectrometry (HRMS) data were obtained by
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column chromatography on silica gel (eluted with EtOAc/hexanes,
with water and brine, dried over anhydrous MgSO4, filtered, and
concentrated to afford 315 mg as a semisolid. The crude compound
was diluted with DCM (10 mL), and TFA (2 mL) was added at 0
°C. The reaction mixture was removed from the ice bath, and
stirring continued at RT. After 4 h, the reaction mixture cooled to 0
°C, and pH was adjusted (neutral) using triethylamine. The organic
layer was washed with water and brine, dried over anhydrous
MgSO4, filtered, concentrated, and separated by column chromatog-
raphy on silica gel (eluted with EtOAc/hexanes, 2:5) to afford 210
26
1:1) to afford 92 mg (15%) as a semisolid. [α]D = −126.2 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.91−5.78 (m, 1 H),
5.20−5.05 (m, 2 H), 4.51 (bs, 1 H), 4.45 (t, J = 6.0 Hz, 1 H), 3.52
(t, J = 6.4 Hz, 2 H), 2.66−2.54 (m, 1 H), 2.17 (dd, J = 0.8, 6.0 Hz,
2 H), 1.88 (t, J = 6.0 Hz, 1 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 171.6, 133.5, 118.2, 72.8, 64.1, 37.2, 28.6 ppm;
νmax(neat)/cm−1: 3302, 3016, 2995, 1564, 1521, 1376, 1093, 785,
643 cm−1; HRMS (ESI) m/z: [M]+ calcd for C7H12NO2 142.0868;
found 142.0869.
26
mg (85% overall two steps) of 8b as a white solid. [α]D = +152.0
1
(3R,5R,6S)-3-Allyl-5,6-diphenylmorpholin-2-one (7, Table 1,
Entry 1). To a stirred solution of tert-butyl (2S,3R)-6-oxo-2,3-
diphenylmorpholine-4-carboxylate1 (300 mg, 0.849 mmol, 1 equiv)
and allyl iodide (388 μL, 4.243 mmol, 5 equiv) in THF (5 mL) was
added lithium bis(trimethylsilyl)amide (1019 μL, 1.019 mmol, 1.2
equiv, 1 M solution in THF) dropwise via syringe at −78 °C. After
40 min, the reaction mixture was quenched with sat. NH4Cl
solution. The organic layer was washed with water and brine, dried
over anhydrous MgSO4, filtered, and concentrated to afford 286 mg
(85%) as a white solid. The crude compound was diluted with
DCM (10 mL) and added TFA (2 mL) at 0 °C. The reaction
mixture was removed from the ice bath, and stirring continued at
RT. After 4 h, the reaction mixture cooled to 0 °C, and pH was
adjusted (neutral) using triethylamine. The organic layer was
washed with water and brine, dried over anhydrous MgSO4, filtered,
concentrated, and separated by column chromatography on silica gel
(eluted with EtOAc/hexanes, 2:5) to afford 199 mg (81% overall
(c 1.0, CHCl3); Mp 96−98 °C; H NMR (400 MHz, CDCl3): δ
7.48−7.30 (m, 5H), 4.49−4.28 (m, 3 H), 4.01−3.92 (m, 1 H),
2.91−2.78 (m, 2 H), 2.38 (bs, 1 H), 2.08 (s, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 169.7, 138.1, 129.1, 128.6, 127.1, 77.4,
77.1, 76.8, 73.5, 72.1, 54.3, 53.1, 22.5 ppm; νmax(neat)/cm−1: 2970,
2890, 1603, 1456, 1314, 1225, 1039, 757, 646 cm−1; HRMS (ESI)
m/z: [M]+ calcd for C13H14NO2 216.1025; found 216.1029.
(3S,5S)-3-((E)-But-2-enyl)-5-phenylmorpholin-2-one (8c, Table
1, Entry 4). To a stirred solution of (S)-tert-butyl 2-oxo-5-
phenylmorpholine-4-carboxylate2 (300 mg, 1.08 mmol, 1 equiv) in
THF (5 mL) and DME (5 mL) was added sodium bis-
(trimethylsilyl) amide (594 μL, 1.19 mmol, 1.1 equiv, 2 M solution
in THF) dropwise via syringe at −78 °C. After 20 min, neat crotyl
bromide (2.16 mmol, 2 equiv) was added dropwise. The reaction
was quenched with sat. NH4Cl after 1.5 h. The organic layer was
washed with water and brine, dried over anhydrous MgSO4, filtered,
and concentrated to afford 315 mg as a white solid. The crude
compound was diluted with DCM (10 mL) and added TFA (2 mL)
at 0 °C. The reaction mixture was removed from the ice bath, and
stirring continued at RT. After 4 h, the reaction mixture cooled to 0
°C, and pH was adjusted (neutral) using triethylamine. The organic
layer was washed with water and brine, dried over anhydrous
MgSO4, filtered, concentrated, and separated by column chromatog-
raphy on silica gel (eluted with EtOAc/hexanes, 2:5) to afford 216
26
two steps) of 7 as a white solid. [α]D = +260.0 (c 1.0, CHCl3);
1
Mp 118−120 °C; H NMR (400 MHz, CDCl3): δ 7.22−7.15 (m,
6H), 7.00−6.95 (m, 2 H), 6.92−6.88 (m, 2 H), 5.88−5.80 (m, 1
H), 5.67 (d, J = 3.2 Hz, 1 H), 5.19−5.13 (m, 2 H), 4.73−4.63 (m,
1H), 4.08−4.01 (m, 1H), 2.84−2.69 (m, 2H), 2.00 (bs, 1 H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ 170.6, 137.0, 135.0, 133.9,
128.4, 128.2, 128.1, 127.7, 127.7, 127.2, 119.6, 85.2, 77.5, 77.1, 76.8,
56.8, 56.0, 37.9 ppm; νmax(neat)/cm−1: 3331, 2981, 1700, 1456,
1196, 1036, 703 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C19H20NO2 294.1494; found 294.1491.
26
mg (86% overall two steps) of 8c as a white solid. [α]D = +82.0 (c
1
1.0, CHCl3); Mp 82−84 °C; H NMR (400 MHz, CDCl3): δ 7.48−
7.29 (m, 5H), 5.66−5.43 (m, 2 H), 4.41−4.23 (m, 3 H), 3.84−3.74
(m, 1 H), 2.63−2.53 (m, 2 H), 1.98 (bs, 1 H), 1.69−1.63 (m, 2 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 138.6, 130.5,
128.9, 128.5, 127.1, 126.0, 77.5, 77.2, 76.8, 73.2, 55.1, 53.1, 35.2,
18.1 ppm; νmax(neat)/cm−1: 2981, 1603, 1453, 1164, 912, 647 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C14H18NO2 232.1338; found
232.1337.
(3S,5S)-3-Allyl-5-phenylmorpholin-2-one (8a, Table 1, Entry 2).
To a stirred solution of (S)-tert-butyl 2-oxo-5-phenylmorpholine-4-
carboxylate2 (300 mg, 1.08 mmol, 1 equiv) in THF (5 mL) and
DME (5 mL) was added sodium bis(trimethylsilyl) amide (594 μL,
1.19 mmol, 1.1 equiv, 2 M solution in THF) dropwise via syringe at
−78 °C. After 20 min, neat allyl bromide (2.16 mmol, 2 equiv) was
added dropwise. The reaction was quenched with sat. NH4Cl after
1.5 h. The organic layer was washed with water and brine, dried
over anhydrous MgSO4, filtered, and concentrated to afford 305 mg
(90%) as a white solid. The crude compound was diluted with
DCM (10 mL), and TFA (2 mL) was added at 0 °C. The reaction
mixture was removed from the ice bath, and stirring continued at
RT. After 4 h, the reaction mixture was cooled to 0 °C, and the pH
was adjusted to neutral using triethylamine. The organic layer was
washed with water and brine, dried over anhydrous MgSO4, filtered,
concentrated, and separated by column chromatography on silica gel
(eluted with EtOAc/hexanes, 2:5) to afford 200 mg (85% overall
(3S,5S)-3-(2-Methylallyl)-5-phenylmorpholin-2-one (8d, Table 1,
Entry 5). To a stirred solution of (S)-tert-butyl 2-oxo-5-phenyl-
morpholine-4-carboxylate2 (300 mg, 1.08 mmol, 1 equiv) in THF (5
mL) and DME (5 mL) was added sodium bis(trimethylsilyl) amide
(594 μL, 1.19 mmol, 1.1 equiv, 2 M solution in THF) dropwise via
syringe at −78 °C. After 20 min, neat 3-bromo-2-methylprop-1-ene
(2.16 mmol, 2 equiv) was added dropwise. The reaction was
quenched with sat. NH4Cl after 1.5 h. The organic layer was washed
with water and brine, dried over anhydrous MgSO4, filtered, and
concentrated to afford 315 mg as a white solid. The crude
compound was diluted with DCM (10 mL) and added TFA (2 mL)
at 0 °C. The reaction mixture was removed from the ice bath, and
stirring continued at RT. After 4 h, the reaction mixture cooled to 0
°C, and pH was adjusted (neutral) using triethylamine. The organic
layer was washed with water and brine, dried over anhydrous
MgSO4, filtered, concentrated, and separated by column chromatog-
raphy on silica gel (eluted with EtOAc/hexanes, 2:5) to afford 225
26
two steps) of 8a as a white solid. [α]D = −7.6 (c 1.0, CHCl3); Mp
1
64−66 °C; H NMR (400 MHz, CDCl3): δ 7.50−7.31 (m, 5H),
5.88−5.80 (m, 1 H), 5.24−5.15 (m, 2 H), 4.44−4.28 (m, 3 H), 3.86
(dd, J = 3.6 Hz, 1 H), 2.72−2.62 (m, 2H), 1.97 (bs, 1 H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ 171.0, 133.6, 129.0, 126.9,
119.7, 77.3, 77.1, 76.8, 73.2, 54.7, 53.1, 36.4 ppm; νmax(neat)/cm−1:
3323, 2992, 1733, 1464, 1182, 1025, 698 cm−1; HRMS (ESI) m/z:
[M]+ calcd for C13H16NO2 218.1176; found 218.1175.
26
mg (90% overall two steps) of 8d as a solid. [α]D = −106.8 (c 1.0,
25
1
CHCl3); Mp 92−94 °C; [α]D −12.3 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3): δ 7.43−7.31 (m, 5H), 4.92−4.81 (m, 1 H),
4.80−4.75 (m, 1 H), 4.36−4.27 (m, 3 H), 3.97−3.94 (m, 1 H),
2.66−2.59 (m, 1 H), 1.99 (bs, 1 H), 1.75 (s, 3 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.1, 141.1, 138.1, 128.9, 128.6,
127.2, 115.2, 77.43, 77.1, 76.8, 73.9, 53.6, 52.4, 40.4, 21.6 ppm;
νmax(neat)/cm−1: 2971, 1648, 1455, 1216, 1039, 898, 596 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C14H18NO2 232.1338; found
232.1338.
(3S,5S)-5-Phenyl-3-(prop-2-ynyl)morpholin-2-one (8b, Table 1,
Entry 3). To a stirred solution of (S)-tert-butyl 2-oxo-5-phenyl-
morpholine-4-carboxylate2 (300 mg, 1.08 mmol, 1 equiv) in THF (5
mL) and DME (5 mL) was added sodium bis(trimethylsilyl) amide
(594 μL, 1.19 mmol, 1.1 equiv, 2 M solution in THF) dropwise via
syringe at −78 °C. After 20 min, 80% propargyl bromide (2.16
mmol, 2 equiv) in toluene was added dropwise. The reaction was
quenched with sat. NH4Cl after 1.5 h. The organic layer was washed
2081
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Article
(3S,5S)-3-(3-Methylbut-2-enyl)-5-phenylmorpholin-2-one (8e,
Table 1, Entry 6). To a stirred solution of (S)-tert-butyl 2-oxo-5-
phenylmorpholine-4-carboxylate2 (300 mg, 1.08 mmol, 1 equiv) in
THF (5 mL) and DME (5 mL) was added sodium bis-
(trimethylsilyl) amide (594 μL, 1.19 mmol, 1.1 equiv, 2 M solution
in THF) dropwise via syringe at −78 °C. After 20 min, neat 1-
bromo-3-methylbut-2-ene (2.16 mmol, 2 equiv) was added
dropwise. The reaction was quenched with sat. NH4Cl after 1.5 h.
The organic layer was washed with water and brine, dried over
anhydrous MgSO4, filtered, and concentrated to afford 315 mg as a
white solid. The crude compound was diluted with DCM (10 mL)
and added TFA (2 mL) at 0 °C. The reaction mixture was removed
from the ice bath, and stirring continued at RT. After 4 h, the
reaction mixture cooled to 0 °C, and pH was adjusted (neutral)
using triethylamine. The organic layer was washed with water and
brine, dried over anhydrous MgSO4, filtered, concentrated, and
separated by column chromatography on silica gel (eluted with
EtOAc/hexanes, 2:5) to afford 212 mg (80% overall two steps) of
8e as a solid. [α]D = −263.2 (c 1.0, CHCl3); Mp 96−98 °C; H
NMR (400 MHz, CDCl3): δ 7.43−7.30 (m, 5H), 5.20−5.12 (m, 1
H), 4.92−4.81 (m, 1 H), 4.80−4.75 (m, 1 H), 4.36−4.27 (m, 3 H),
3.97−3.94 (m, 1 H), 3.83−3.77 (m, 1 H), 2.74−2.51 (m, 2 H), 1.91
(bs, 1 H), 1.71 (s, 3 H), 1.64 (s, 3 H) ppm; 13C{1H} NMR (100
MHz, CDCl3): δ 171.3, 138.5, 136.9, 128.9, 128.5, 127.1, 119.3,
77.4, 77.1, 76.8, 73.5, 55.8, 53.2, 30.8, 25.9, 18.1 ppm; νmax(neat)/
cm−1: 2971, 1746, 1387, 1174, 1050, 697, 607 cm−1; HRMS (ESI)
m/z: [M]+ calcd for C15H20NO2 246.1494; found 246.1498.
General Procedure A: The TFA Mediated aza-Prins
Reaction. A round-bottomed flask was charged with aldehyde
(0.5 equiv) and dichloromethane (10 mL). To the resulting
suspension was added neat TFA (1 mmol, 2 equiv). After stirring
the mixture for 15 min at room temperature, corresponding amine
derivative (0.5 mmol, 1.00 equiv) in dichloromethane (3 mL) was
added, and the resulting mixture was stirred for 12 h. After this
time, the solvent was concentrated completely. The resulting
material was diluted with methanol (15 mL), and K2CO3 (excess,
5 equiv) was added and stirred for 3 h. The solvent was removed
and diluted with DCM. The organic layer was separated, and the
aqueous layer was extracted with dichloromethane (2 × 10 mL).
The combined organic layers were dried over magnesium sulfate,
filtered, concentrated in vacuo, and purified by chromatography
(silica gel 100−200 mesh, 30:70 EtOAc/Hexane).
H), 4.59 (d, J = 4.4 Hz, 1 H), 4.17 (dd, J = 3.6, 8.8 Hz, 1 H), 4.05
(sep, J = 6.4 Hz, 1 H), 3.04−2.96 (m, 1H), 2.30−2.23 (m, 1 H),
2.09−1.94 (m, 1 H), 1.58−1.40 (m, 6 H), 1.34−1.19 (m, 3 H),
1.15−1.10 (m, 1 H), 0.78 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 171.0, 135.7, 135.5, 129.9, 128.3, 128.1,
127.9, 127.6, 83.8, 77.4, 77.1, 76.8, 64.9, 61.8, 54.5, 54.3, 34.6, 33.5,
33.2, 19.9, 14.2 ppm; νmax(neat)/cm−1: 2981, 1767, 1455, 1130,
1042, 753, 658 cm−1; HRMS (ESI) m/z: [M]+ calcd for C23 H28 O3
N 366.2064; found 366.2064.
( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 8 - H y d r o x y - 6 - p h e n e t h y l - 3 , 4 -
diphenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9b, Table
2, Entry 3). Following the general procedure A, the title compound
9b was prepared from compound 7a (146 mg) and 3-phenyl
26
propionaldehyde as a white solid (173 mg, 81%). [α]D = −421.0
1
(c 1.0, CHCl3); Mp 136−138 °C; H NMR (400 MHz, CDCl3): δ
7.27−7.09 (m, 7 H), 7.04 (t, J = 7.2 Hz, 2 H), 6.94 (d, J = 7.2 Hz,
4 H), 6.73 (d, J = 8.0 Hz, 2 H), 5.55 (d, J = 4.0 Hz, 1 H), 4.52 (dd,
J = 4.0, 14.4 Hz, 2 H), 4.20 (dd, J = 2.4, 10 Hz, 1 H), 4.01−3.92
(m, 1 H), 3.01−2.94 (m, 1H), 2.90 (bs, 1 H), 2.66−2.53 (m, 1 H),
2.38−2.20 (m, 2 H), 2.02−1.77 (m, 2 H), 1.62−1.39 (m, 3 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 141.6, 135.6,
135.5, 129.6, 128.1, 128.1, 128.0, 128.0, 127.8, 127.6, 127.3, 125.6,
83.4, 77.9, 77.6, 77.2, 63.6, 62.0, 54.6, 54.3, 34.8, 33.2, 32.7, 32.6
ppm; νmax(neat)/cm−1: 2933, 1738, 1626, 1221, 953, 732 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C28 H30 O3 N 428.2220; found
428.2219.
26
1
( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 8 - H y d r o x y - 3 , 4 - d i p h e n y l - 6 -
undecylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9c, Table 2,
Entry 4). Following the general procedure A, the title compound 9c
was prepared from compound 7a (146 mg) and dodecanal as a
26
white solid (179 mg, 75%). [α]D = +78.0 (c 1.0, CHCl3); Mp
1
126−128 °C; H NMR (400 MHz, CDCl3): δ 7.23−7.13 (m, 4 H),
7.10−7.05 (m, 2 H), 6.96−6.91 (m, 2 H), 6.77−6.73 (m, 2 H), 5.54
(d, J = 4.0 Hz, 1 H), 4.57 (d, J = 4.0 Hz, 1 H), 4.17 (dd, J = 3.2,
8.8 Hz, 1 H), 4.04 (sep, J = 6.0 Hz, 1 H), 3.02−2.93 (m, 1H),
2.32−2.24 (m, 1 H), 2.03−1.93 (m, 1 H), 1.61−1.38 (m, 3 H),
1.33−1.02 (m, 22 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 170.9, 135.7, 135.5, 129.9, 128.3,
128.1, 127.9, 127.5, 83.7, 77.4, 77.0, 76.7, 64.9, 61.9, 54.6, 54.2,
34.6, 33.3, 32.0, 31.2, 29.7, 29.6, 29.4, 26.6, 22.7, 14.2 ppm;
νmax(neat)/cm−1: 2971, 1712, 1457, 1152, 885, 730 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C31 H44 O3 N 478.3316; found 478.3309.
( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 8 - H y d r o x y - 6 - n o n y l - 3 , 4 -
diphenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9d, Table
2, Entry 5). Following the general procedure A, the title compound
9d was prepared from compound 7a (146 mg) and decanal as a
( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 8 - H y d r o x y - 3 , 4 - d i p h e n y l - 6 -
propylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9a, Table 2,
Entry 1). Following the general procedure A, the title compound 9a
was prepared from compound 7a (146 mg) and butanal as a white
26
white solid (164 mg, 73%). [α]D = −52.0 (c 1.0, CHCl3); Mp
26
1
solid (138 mg, 76%). [α]D = −40.0 (c 1.0, CHCl3); Mp 116−118
124−126 °C; H NMR (400 MHz, CDCl3): δ 7.23−7.13 (m, 4 H),
1
°C; H NMR (400 MHz, CDCl3): δ 7.22−7.20 (m, 2 H), 7.18−
7.10−7.04 (m, 2 H), 6.96−6.90 (m, 2 H), 6.77−6.72 (m, 2 H), 5.52
(d, J = 4.0 Hz, 1 H), 4.57 (d, J = 4.0 Hz, 1 H), 4.17 (dd, J = 3.2,
8.8 Hz, 1 H), 4.09−4.00 (m, 1 H), 3.00−2.93 (m, 1H), 2.30−2.24
(m, 1 H), 2.02−1.93 (m, 1 H), 1.46−1.38 (m, 1 H), 1.35−1.06 (m,
15 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 170.9, 135.7, 135.5, 129.9, 128.3, 128.1, 127.9, 127.5,
83.7, 77.4, 77.1, 76.8, 64.9, 61.9, 54.6, 54.2, 34.6, 33.3, 31.9, 31.2,
29.6, 29.3, 26.7, 22.8, 14.2 ppm; νmax(neat)/cm−1: 2983, 1738, 1454,
1224, 703 cm−1; HRMS (ESI) m/z: [M]+ calcd for C29 H40 O3 N
450.3003; found 450.3001.
7.13 (m, 5 H), 7.10−7.05 (m, 2 H), 6.96−6.91 (m, 2 H), 6.79−6.74
(m, 2 H), 5.53 (d, J = 4.4 Hz, 1 H), 4.59 (d, J = 4.4 Hz, 1 H), 4.17
(dd, J = 3.6, 8.8 Hz, 1 H), 4.05 (sep, J = 6.4 Hz, 1 H), 3.04−2.96
(m, 1H), 2.30−2.23 (m, 1 H), 2.09−1.94 (m, 1 H), 1.58−1.40 (m,
6 H), 1.34−1.19 (m, 3 H), 1.15−1.10 (m, 1 H), 0.78 (t, J = 7.2 Hz,
3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 135.7,
135.5, 129.8, 128.3, 128.1, 128.0, 127.9, 127.6, 83.7, 77.4, 77.2, 77.0,
76.7, 64.9, 61.9, 54.5, 54.2, 34.6, 33.5, 33.2, 19.9, 14.1 ppm;
νmax(neat)/cm−1: 2981, 1730, 1355, 1044, 921, 655 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C23 H28 O3 N: 366.2064; found:
366.2064. Compound 9a was also prepared using the same method
starting from 7a (146 mg) and butanal diethyl acetal (73 mg) in
132 mg, 73% yield (Table 2, entry 11). All data were in agreement
with those presented above.
( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 6 - H e p t y l - 8 - h y d r o x y - 3 , 4 -
diphenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9e, Table
2, Entry 6). Following the general procedure A, the title compound
was prepared from compound 5 (146 mg) and octanal as a white
26
solid (151 mg, 72%). [α]D = +124.0 (c 1.0, CHCl3); Mp 108−110
1
°C; H NMR (400 MHz, CDCl3): δ 7.22−7.13 (m, 4 H), 7.07 (t, J
( 3 R , 4 S , 6 R , 8 S , 9 a S ) - 8 - H y d r o x y - 3 , 4 - d i p h e n y l - 6 -
propylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9a′, Table 2,
Entry 2). Following the general procedure A, the title compound 9a′
was prepared from compound 7b (146 mg) (opposite isomer of 7a)
= 8 Hz, 2 H), 6.97−6.93 (m, 2 H), 6.79−6.73 (m, 2 H), 5.53 (d, J
= 4.0 Hz, 1 H), 4.57 (d, J = 4.0 Hz, 1 H), 4.17 (dd, J = 3.2, 8.8 Hz,
1 H), 4.04 (sep, J = 6.0 Hz, 1 H), 3.02−2.94 (m, 1H), 2.31−2.22
(m, 1 H), 2.03−1.93 (m, 1 H), 1.87 (bs, 1 H), 1.58−1.38 (m, 3 H),
1.32−1.05 (m, 12 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.0, 135.7, 135.5, 129.9, 128.3,
128.1, 127.9, 127.6, 83.8, 77.4, 77.3, 77.1, 76.8, 64.8, 61.9, 54.6,
26
and butanal as a white solid (150 mg, 82%). [α]D = +360.00 (c
1.0, MeOH); Mp 124−126 oC; 1H NMR (400 MHz, CDCl3): δ
7.22−7.20 (m, 2 H), 7.18−7.13 (m, 5 H), 7.10−7.05 (m, 2 H),
6.96−6.91 (m, 2 H), 6.79−6.74 (m, 2 H), 5.53 (d, J = 4.4 Hz, 1
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54.2, 34.6, 33.3, 31.8, 31.2, 29.5, 29.3, 26.7, 22.7, 14.1 ppm;
νmax(neat)/cm−1: 2981, 1740, 1382, 1071, 956, 696 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C27 H36 O3 N 422.2690; found 422.2688.
( 3 S , 4 R , 6 R , 8 R , 9 a R ) - 6 - B e n z h y d r y l - 8 - h y d r o x y - 3 , 4 -
diphenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (9f, Table
2, Entry 7). Following the general procedure A, the title compound
9e was prepared from compound 7a (146 mg) and diphenyl
(d, J = 4.0 Hz, 1 H), 4.38−4.18 (m, 2 H), 3.05−2.97 (m, 1 H),
2.67−2.57 (m, 1 H), 2.46−2.32 (m, 1 H), 1.96 (s, 3H), 1.90−1.78
(m, 1 H), 1.70−1.55 (m, 3 H), 1.71.37 (m, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 170.5, 169.3, 141.6, 141.5, 135.5,
135.4, 129.8, 128.4, 128.4, 128.3, 128.3, 128.3, 128.1, 127.9, 127.7,
125.9, 84.1, 77.4, 77.3, 77.1, 76.8, 62.6, 54.4, 42.9, 32.8, 32.4, 31.8,
31.2, 23.6 ppm; νmax(neat)/cm−1: 2980, 1738, 1544, 1373, 1235,
1020, 694 cm−1; HRMS (ESI) m/z: [M]+ calcd for C30 H33 O3 N2
469.2486; found 469.2481.
26
acetaldehyde as a white solid (191 mg, 78%). [α]D = +125.0 (c
1.0, CHCl3); Mp 140−142 °C; 1H NMR (400 MHz, CDCl3): δ
7.21−7.01 (m, 14 H), 6.93−6.85 (m, 2 H), 6.53−6.49 (m, 4 H),
5.32 (d, J = 4.0 Hz, 1 H), 4.65 (d, J = 4.0 Hz, 1 H), 4.46 (dd, J =
4.0 Hz, 1 H), 4.16 (d, J = 12.0 Hz, 1 H), 3.76−3.73 (m, 1H),
2.41−2.32 (m, 1 H), 2.14−2.03 (m, 1 H), 1.58−1.51 (m, 1 H),
1.41−1.32 (m, 1 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
170.1, 142.5, 141.9, 135.3, 134.3, 130.3, 129.0, 128.5, 128.3, 127.8,
127.7, 127.7, 126.9, 126.8, 84.1, 77.4, 77.1, 76.7, 63.9, 61.8, 58.3,
54.8, 52.7, 33.4, 29.3 ppm; νmax(neat)/cm−1: 2981, 1726, 1382,
1073, 957, 695 cm−1; HRMS (ESI) m/z: [M]+ calcd for C33 H32 O3
N 490.2377; found 490.2369.
N - ( ( 3 R , 4 S , 6 R , 8 S , 9 a S ) - 1 - O x o - 6 - p h e n e t h y l - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10a′,
Table 3, Entry 2). Following the general procedure B, the title
compound 10a′ (enantiomer of 10a) was prepared from compound
7b (146 mg) and 3-phenylpropionaldehyde as a white solid (178
26
1
mg, 76%). [α]D = +120.00 (c 1.0, MeOH); Mp 172−174 °C; H
NMR (400 MHz, CDCl3): δ 7.22−7.02 (m, 10 H), 6.97−6.92 (m,
3 H), 6.74−6.70 (m, 2 H), 5.51 (d, J = 4.0 Hz, 1 H), 5.37 (d, J =
8.3 Hz, 1 H), 4.53 (d, J = 4.0 Hz, 1 H), 4.38−4.18 (m, 2 H), 3.05−
2.97 (m, 1 H), 2.67−2.57 (m, 1 H), 2.46−2.32 (m, 1 H), 1.96 (s,
3H), 1.90−1.78 (m, 1 H), 1.70−1.55 (m, 3 H), 1.71−1.37 (m, 1 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.4, 168.3, 140.5,
134.5, 134.4, 128.7, 127.4, 127.4, 127.3, 127.2, 127.1, 126.9, 126.6,
124.9, 83.0, 76.3, 76.1, 75.8, 61.6, 53.4, 53.3, 41.9, 31.8, 31.4, 30.7,
30.2, 22.6 ppm; νmax(neat)/cm−1: 2981, 1733, 1355, 1114, 751, 698
cm−1; HRMS (ESI) m/z: [M]+ calcd for C30 H33 O3 N2 469.2486;
found 469.2481.
( 3 S , 4 R , 6 R , 8 R , 9 a R ) - E t h y l 8 - h y d r o x y - 1 - o x o - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazine-6-carboxylate (9g,
Table 2, Entry 8). Following the general procedure A, the title
compound was prepared from compound 7a (146 mg) and ethyl
26
glyoxylate (0.5 mmol) as a white solid (175 mg, 91%). [α]D
=
−226.0 (c 1.0, CHCl3); Mp 196−198 °C; 1H NMR (400 MHz,
CDCl3): δ 7.22−7.03 (m, 8H), 6.88 (d, J = 7.2 Hz, 2 H), 5.79 (d, J
= 3.6 Hz, 1 H), 4.89 (dd, J = 2.8, 8.8 Hz, 1 H), 4.27 (m, 2H),
3.83−3.66 (m, 2H), 3.57−3.48 (m, 1H), 3.42 (d, J = 7.6 Hz, 1 H),
3.56 (d, J = 12.8 Hz, 1 H), 2.20−2.19 (m, 3H), 1.06 (t, J = 7.2 Hz,
3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 174.6, 170.8,
135.4, 134.2, 129.5, 128.1, 128.0, 128.0, 128.0, 127.8, 126.7, 83.5,
77.3, 77.0, 76.6, 64.6, 64.2, 61.1, 57.4, 50.1, 35.4, 31.7, 13.6, 13.6,
13.6 ppm; νmax(neat)/cm−1: 3481, 2932, 1699, 1232, 1052, 697
cm−1; HRMS (ESI) m/z: [M]+ calcd for C23 H26 O5 N 396.1805;
found 396.1806.
N - ( ( 3 S , 4 R , 6 R , 8 S , 9 a R ) - 6 - H e p t y l - 1 - o x o - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10b,
Table 3, Entry 3). Following the general procedure B, the title
compound was prepared from compound 7a (146 mg) and octanal
26
as a white solid (168 mg, 73%). [α]D = −54.0 (c 1.0, CHCl3); Mp
1
172−174 °C; H NMR (400 MHz, CDCl3): δ 7.23−7.06 (m, 6 H),
6.94−6.91 (m, 2 H), 6.77−6.72 (m, 2 H), 5.49 (d, J = 4.0 Hz, 1
H), 5.32 (bs, 1 H), 4.54 (d, J = 4.0 Hz, 1 H), 4.31−4.16 (m, 2 H),
2.96−2.92 (m, 1 H), 2.36−2.31 (m, 1 H), 1.96 (s, 3H), 1.81−1.77
(m, 1 H), 1.55−1.49 (m, 2 H), 1.40−1.08 (m, 11 H), 0.86 (t, J =
7.2 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.5,
169.2, 135.6, 135.5, 129.8, 128.3, 128.2, 128.1, 127.9, 127.6, 84.2,
77.4, 77.1, 76.7, 62.3, 54.6, 54.3, 42.9, 32.2, 31.8, 31.0, 30.3, 29.5,
29.3, 26.7, 23.6, 22.7, 14.2 ppm; νmax(neat)/cm−1: 2981, 1733, 1373,
1132, 702 cm−1; HRMS (ESI) m/z: [M]+ calcd for C29 H39 O3 N2
463.2955; found 463.2951.
(3S,4R,6R,8R,9aR)-1-Oxo-3,4-diphenyloctahydropyrido[2,1-c]-
[1,4]oxazine-6,8-carboxylic Anhydride (9h, Table 2, Entry 9).
Following the general procedure A, the title compound was
prepared from compound 7a (146 mg) and glyoxylic acid as a
26
white solid (104 mg, 60%). [α]D = +40.0 (c 1.0, MeOH); Mp
1
240−242 °C; H NMR (400 MHz, CDCl3): δ 7.14−7.05 (m, 6 H),
6.95−6.88 (m, 4 H), 5.72 (d, J = 5.6 Hz, 1 H), 5.00 (t, J = 5.6 Hz,
1 H), 4.47 (d, J = 4.8 Hz, 1 H), 4.12 (dd, J = 5.6 Hz, 1 H), 3.35 (d,
J = 4.8 Hz, 1 H), 2.62−2.54 (m, 1 H), 2.30−2.18 (m, 2 H), 1.93
(m, 1 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 173.4, 170.6,
136.1, 134.2, 129.1, 128.2, 128.2, 127.9, 127.9, 126.7, 126., 79.6,
77.4, 77.1, 76.7, 76.5, 65.8, 57.8, 52.8, 36.9, 31.2 ppm; νmax(neat)/
cm−1: 2825, 1756, 1218, 1049, 956, 771, 678 cm−1; HRMS (ESI)
m/z: [M]+ calcd for C21 H20 O4 N 350.1387; found 350.1390.
General Procedure B for the aza-Prins−Ritter Reaction. A
round-bottomed flask was charged with an aldehyde (0.5 equiv) and
CH3CN (10 mL). To the resulting suspension was added anhydrous
pTSA (0.75 mmol, 1.5 equiv). After stirring the mixture for 15 min
at room temperature, an amine derivative (7a or 7b, 0.5 mmol, 1.00
equiv) in CH3CN (3 mL) was added, and the resulting mixture was
stirred for 12 h at 35 °C using a solid heating block. The solvent
was removed and diluted with DCM (20 mL) followed by sat.
NaHCO3 solution (20 mL). The organic layer was separated, and
the aqueous layer was extracted with dichloromethane (2 × 10 mL).
The combined organic layers were dried over magnesium sulfate,
filtered, concentrated in vacuo, and purified by chromatography
(silica gel 100−200 mesh, 50:49:1 EtOAc/Hexane/Et3N).
N - ( ( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 6 - N o n y l - 1 - o x o - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10c,
Table 3, Entry 4). Following the general procedure B, the title
compound 10c was prepared from compound 7a (146 mg) and
26
decanal as a white solid (191 mg, 78%). [α]D = −132.0 (c 1.0,
1
CHCl3); Mp 173−175 °C; H NMR (400 MHz, CDCl3): δ 7.22−
7.03 (m, 6 H), 6.95−6.90 (m, 2 H), 6.78−6.72 (m, 2 H), 5.47 (d, J
= 4.0 Hz, 1 H), 5.38 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 4.0 Hz, 1
H), 4.28−4.18 (m, 2 H), 2.98−2.93 (m, 1 H), 2.38−2.30 (m, 1 H),
1.97 (s, 3H), 1.83−1.77 (m, 1 H), 1.57−1.49 (m, 1 H), 1.40−1.02
(m, 16 H), 0.87 (d, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR (100
MHz, CDCl3): δ 170.5, 169.2, 135.6, 135.5, 129.8, 128.3, 128.2,
128.1, 127.9, 127.6, 84.2, 77.4, 77.1, 76.7, 62.3, 54.6, 54.3, 42.9,
32.2, 31.9, 31.0, 30.3, 29.6, 29.4, 26.7, 23.6, 22.7, 14.2 ppm;
νmax(neat)/cm−1: 2971, 1733, 1319, 1053, 954, 768 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C31 H43 O3 N2 491.3268; found
491.3259.
N - ( ( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 1 - O x o - 6 - p e n t y l - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10d,
Table 3, Entry 5). Following the general procedure B, the title
compound 10d was prepared from compound 7a (146 mg) and
26
hexanal as a white solid (163 mg, 75%). [α]D = −120.0 (c 1.0,
N - ( ( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 1 - O x o - 6 - p h e n e t h y l - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10a,
Table 3, Entry 1). Following the general procedure B, the title
1
CHCl3); Mp 156−158 °C; H NMR (400 MHz, CDCl3): δ 7.22−
7.06 (m, 6 H), 6.96−6.91 (m, 2 H), 6.78−6.72 (m, 2 H), 5.49 (d, J
= 4.0 Hz, 1 H), 5.32 (bs, 1 H), 4.55 (d, J = 4.0 Hz, 1 H), 4.31−
4.16 (m, 2 H), 2.98−2.92 (m, 1 H), 2.38−2.29 (m, 1 H), 1.96 (s,
3H), 1.87−1.83 (m, 1 H), 1.55−1.49 (m, 2 H), 0.81 (t, J = 7.2 Hz,
3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 169.2,
135.6, 135.4, 129.8, 128.3, 128.2, 128.1, 128.0, 128.0, 127.9, 127.6,
compound 10a was prepared from compound 7a (146 mg) and 3-
26
phenylpropionaldehyde as a white solid (194 mg, 83%). [α]D
=
1
−560.00 (c 1.0, CHCl3); Mp 166−168 °C; H NMR (400 MHz,
CDCl3): δ 7.22−7.02 (m, 10 H), 6.97−6.92 (m, 3 H), 6.74−6.70
(m, 2 H), 5.51 (d, J = 4.0 Hz, 1 H), 5.37 (d, J = 8.3 Hz, 1 H), 4.53
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84.2, 77.4, 77.3, 77.1, 76.7, 62.3, 54.6, 54.3, 42.9, 32.2, 31.7, 31.0,
30.2, 26.4, 23.6, 22.6, 22.6, 14.0 ppm; νmax(neat)/cm−1: 2981, 1717,
1237, 1042, 753, 700 cm−1; HRMS (ESI) m/z: [M]+ calcd for C27
H35 O3 N2 435.2642; found 435.2641.
crude product, which was purified by column chromatography (silica
gel 100−200 mesh; 5:95 EtOAc/Hexane).
General Procedure D for the O-Tosyl Azabicyclic Deriva-
tives via aza-Prins Reaction. A round-bottomed flask was
charged with aldehyde (0.5 equiv) and CH3CN (10 mL). To the
resulting suspension was added anhydrous PTSA (0.75 mmol, 1.5
equiv). After stirring the mixture for 15 min at room temperature,
the corresponding amine derivative (0.5 mmol, 1.00 equiv) in
CH3CN (3 mL) was added, and the resulting mixture was stirred for
12 h. After completion of the reaction, the solvent was concentrated.
The resulting crude compound was treated with aqueous sodium
bicarbonate (5 mL), and the product was extracted with
dichloromethane (2 × 10 mL). The organic layer was washed
with brine (5 mL), dried over MgSO4, and evaporated to leave the
crude product, which was purified by column chromatography (silica
gel 100−200 mesh; 5:95 EtOAc/Hexane).
N - ( ( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 1 - O x o - 3 , 4 - d i p h e n y l - 6 -
propyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10e,
Table 3, Entry 6). Following the general procedure B, the title
compound 10e was prepared from compound 7a (146 mg) and
26
butanal as a white solid (152 mg, 74%). [α]D = −63.0 (c 1.0,
1
CHCl3); Mp 162−164 °C; H NMR (400 MHz, CDCl3): δ 7.22−
7.03 (m, 6 H), 6.95−6.90 (m, 2 H), 6.78−6.72 (m, 2 H), 5.49 (d, J
= 4.0 Hz, 1 H), 5.32 (bs, 1 H), 4.55 (d, J = 4.0 Hz, 1 H), 4.31−
4.16 (m, 2 H), 2.98−2.92 (m, 1 H), 2.38−2.20 (m, 1 H), 1.96 (s,
3H), 1.81−1.77 (m, 1 H), 1.40−1.22 (m, 4 H), 0.75 (t, J = 7.2 Hz,
3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 169.2,
135.6, 135.5, 129.8, 128.3, 128.2, 128.0, 128.0, 127.6, 84.1, 77.4,
77.2, 77.1, 76.7, 62.3, 54.5, 54.3, 42.9, 32.6, 32.2, 30.9, 23.6, 19.9,
14.1 ppm; νmax(neat)/cm−1: 2981, 1732, 1232, 1035, 912, 694 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C25 H31 O3 N2: 407.2329; found:
407.2325. Compound 10e was also prepared using the same method
starting from 7a (146 mg) and butanal diethyl acetal (73 mg) in
131 mg, 65% yield (Table 3, entry 7). All data were in agreement
with those presented above.
General Procedure E for the aza-Prins−Ritter Reaction. (a)
Using BF3·OEt2: a round-bottomed flask was charged with aldehyde
(0.5 equiv) and CH3CN (10 mL). To the resulting suspension was
added BF3·OEt2 (0.75 mmol, 1.5 equiv). After stirring the mixture
for 15 min at room temperature, the corresponding amine derivative
(0.5 mmol, 1.00 equiv) in CH3CN (3 mL) was added, and the
resulting mixture was stirred for 12 h. After completion of the
reaction, the solvent was concentrated. The resulting crude
compound was treated with aqueous sodium bicarbonate (5 mL)
and the product was extracted with dichloromethane (2 × 10 mL).
The organic layer was washed with brine (5 mL), dried over
MgSO4, and evaporated to leave the crude product, which was
purified by column chromatography (silica gel 100−200 mesh;
50:49:1 EtOAc/Hexane/Et3N).
(b) Using Sc(OTf)3: a round-bottomed flask was charged with
aldehyde (0.5 equiv) and DCM (10 mL). To the resulting
suspension was added Sc(OTf)3 (0.75 mmol, 1.5 equiv). After
stirring the mixture for 15 min at room temperature, the
corresponding amine derivative (3, 0.5 mmol, 1.00 equiv) in
DCM (3 mL) was added, and the resulting mixture was stirred for
12 h. After completion of the reaction, the solvent was concentrated.
The resulting crude compound was treated with aqueous sodium
bicarbonate (5 mL), and the product was extracted with
dichloromethane (2 × 10 mL). The organic layer was washed
with brine (5 mL), dried over MgSO4, and evaporated to leave the
crude product, which was purified by column chromatography (silica
gel 100−200 mesh; 50:49:1 EtOAc/Hexane/Et3N).
N - ( ( 3 S , 4 R , 6 S , 8 R , 9 a R ) - 6 - B e n z y l - 1 - o x o - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10f,
Table 3, Entry 8). Following the general procedure B, the title
compound 10f was prepared from compound 7a (146 mg) and
26
phenylacetaldehyde as a white solid (186 mg, 82%). [α]D
=
1
−200.00 (c 1.0, MeOH); Mp 156−158 °C; H NMR (400 MHz,
CDCl3): δ 7.22−6.99 (m, 12 H), 6.84−6.79 (m, 2 H), 6.63−6.53
(m, 1 H), 5.47 (d, J = 4.0 Hz, 1 H), 5.35 (bs, 1 H), 4.53 (d, J = 4.0
Hz, 1 H), 4.46−4.34 (m, 1 H), 3.31−3.21 (m, 1 H), 2.72−2.66 (m,
1H), 2.52−2.44 (m, 1 H), 1.95 (s, 3H), 1.88−1.77 (m, 1 H), 1.38−
1.28 (m, 1 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.1,
169.2, 139.1, 135.4, 135.3, 129.7, 129.3, 128.4, 128.2, 128.1, 128.1,
127.8, 127.7, 126.3, 84.5, 77.4, 77.3, 77.1, 76.8, 62.7, 57.4, 54.4,
42.9, 36.3, 32.9, 30.5, 23.5 ppm; νmax(neat)/cm−1: 2981, 1734, 1653,
1454, 1381, 1239, 1071, 698 cm−1; HRMS (ESI) m/z: [M]+ calcd
for C29 H31 O3 N2 455.2329; found 455.2323. Compound 10f was
also prepared using the same method starting from 7a (146 mg) and
styrene oxide (60 mg) in 142 mg, 63% yield (Table 3, entry 9). All
data were in agreement with those presented above.
N - ( ( 3 S , 4 R , 6 R , 8 R , 9 a R ) - 6 - B e n z h y d r y l - 1 - o x o - 3 , 4 -
diphenyloctahydropyrido[2,1-c][1,4]oxazin-8-yl) Acetamide (10g,
Table 3, Entry 10). Following the general procedure B, the title
(4S,6R,8R,9aS)-8-Chloro-6-phenethyl-4-phenylhexahydropyrido-
[2,1-c][1,4]oxazin-1(6H)-one (12a, Table 4, Entry 2). Following the
general procedure C, the title compound 12a was prepared from
compound 8a (109 mg) and 3-phenylpropionaldehyde as a white
compound 10g was prepared from compound 7a (146 mg) and
26
diphenyl acetaldehyde as a white solid (207 mg, 78%). [α]D
=
−113.0 (c 1.0, CHCl3); Mp 148−150 °C; 1H NMR (400 MHz,
CDCl3): δ 7.32−7.02 (m, 15 H), 6.88 (t, J = 7.6 Hz, 2 H), 6.59−
6.45 (m, 3 H), 5.30−5.19 (m, 2 H), 4.67 (d, J = 4.1 Hz, 1 H),
4.51−4.46 (m, 1 H), 4.33 (d, J = 12.8 Hz, 1 H), 3.74−3.61 (m, 1
H), 2.52−2.43 (m, 1 H), 2.05−1.94 (m, 1H), 1.89 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 169.3, 142.3, 141.8,
26
solid (166 mg, 90%). [α]D = +143.0 (c 1.0, CHCl3); Mp 132−134
1
°C; H NMR (400 MHz, CDCl3): δ 7.37−7.14 (m, 8 H), 7.11−
7.08 (m, 2 H), 4.37−4.17 (m, 4 H), 4.11 (dd, J = 3.2, 9.2 Hz, 1 H),
2.89−2.70 (m, 2 H), 2.45−2.20 (m, 3 H), 1.95−1.65 (m, 3H),
1.61−1.54 (m, 1 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
169.2, 141.5, 135.4, 129.4, 129.2, 128.6, 128.6, 128.2, 126.1, 77.4,
77.1, 76.7, 73.9, 55.8, 55.6, 54.2, 53.6, 34.9, 33.9, 33.1, 32.8 ppm;
νmax(neat)/cm−1: 2981, 1726, 1249, 1133, 1020, 698 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C22H2535ClNO2 370.1574; found
370.1570; calcd for C22H2537ClNO2 372.1544; found 372.1536.
(4S,6S,8R,9aS)-8-Chloro-4,6-diphenylhexahydropyrido[2,1-c]-
[1,4]oxazin-1(6H)-one (12b, Table 4, Entry 3). Following the
general procedure C, the title compound 12b was prepared from
compound 8a (109 mg) and benzaldehyde as a white solid (155 mg,
135.3, 134.3, 130.4, 128.9, 128.6, 128.38, 128.0, 127.9, 127.9, 127.8,
127.7, 126.9, 126.8, 84.1, 77.4, 77.1, 76.7, 61.9, 57.7, 54.8, 52.2,
42.2, 30.8, 26.4, 23.5 ppm; νmax(neat)/cm−1: 2982, 1796, 1412,
1096, 978, 693 cm−1; HRMS (ESI) m/z: [M]+ calcd for C35 H35 O3
N2 531.2642; found 531.2637.
General Procedure C for the FeCl3 or FeBr3 Catalyzed aza-
Prins Reaction. A round-bottomed flask was charged with aldehyde
(0.5 equiv) and solvent (DCM for FeCl3 and DBE for FeBr3) (10
mL). To the resulting suspension was added FeCl3 or FeBr3 (0.75
mmol, 1.5 equiv) at 0 °C. After stirring the mixture for 15 min at
the same temperature, the corresponding amine derivative (0.5
mmol, 1.00 equiv) in the appropriate solvent (DCM/DBE) (3 mL)
was added, and the resulting mixture was stirred for 6 h. After
completion of the reaction, the resulting solution was treated with
aqueous sodium bicarbonate (5 mL), and the product was extracted
with dichloromethane (2 × 10 mL). The organic layer was washed
with brine (5 mL), dried over MgSO4, and evaporated to leave the
26
1
91%). [α]D = +78.0 (c 1.0, CHCl3); Mp 164−166 °C; H NMR
(400 MHz, CDCl3): δ 7.56−7.23 (m, 10 H), 4.59−4.51 (m, 2 H),
4.38−4.36 (m, 1 H), 4.25−4.16 (m, 2 H), 3.86 (dd, J = 4.0 Hz, 1
H), 2.55−2.39 (m, 2 H), 2.28−2.21 (m, 1 H), 2.10−2.03 (m, 1 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.3, 139.3, 136.0,
129.4, 129.1, 129.0, 128.0, 127.5, 126.7, 71.5, 56.2, 55.2, 54.6, 53.6,
34.4, 33.8 ppm; νmax(neat)/cm−1: 3031, 1783, 1202, 1163, 1104,
784 cm−1; HRMS (ESI) m/z: [M]+ calcd for C20H2135ClNO2
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342.1261; found 342.1256; calcd for C20H2137ClNO2 344.1231;
found 344.1234.
H), 1.38−1.05 (m, 22 H), 0.87 (t, J = 5.6 Hz, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.4, 136.6, 129.0, 128.7, 128.4, 77.3,
77.1, 76.8, 73.4, 64.5, 56.6, 54.4, 53.9, 32.9, 31.9, 29.6, 29.4, 26.4,
22.7, 14.1 ppm; νmax(neat)/cm−1: 2923, 2853, 1739, 1456, 1230,
1044, 762 cm−1; HRMS (ESI) m/z: [M]+ calcd for C25 H40 O3 N
402.3003; found 402.2999.
( 4 S , 6 S , 8 R , 9 a S ) - 6 - B e n z h y d r y l - 8 - c h l o r o - 4 -
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (12c, Table 4,
Entry 4). Following the general procedure C, the title compound
was prepared from compound 8a (109 mg) and diphenyl
26
acetaldehyde as a white solid (192 mg, 89%). [α]D = +132.0 (c
(4S,6R,8R,9aS)-6-Nonyl-1-oxo-4-phenyloctahydropyrido[2,1-c]-
[1,4]oxazin-8-yl 4-methylbenzenesulfonate (15a, Table 4, Entry
11). Following the general procedure C, the title compound 15a was
prepared from compound 8a (109 mg) and decanal as a white solid
1.0, CHCl3); Mp 120−122 °C; 1H NMR (400 MHz, CDCl3): δ
7.43−7.32 (m, 3 H), 7.26−7.13 (m, 6 H), 7.09−7.00 (m, 4 H),
6.92−6.86 (m, 2 H), 4.37−4.19 (m, 3 H), 4.13−3.97 (m, 3 H),
3.47−3.38 (m, 1 H), 2.53−2.48 (m, 1 H), 2.29 (q, J = 13.2 Hz, 1
H), 1.82−1.65 (m, 2H), 1.61−1.54 (m, 1 H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 169.0, 142.1, 140.9, 134.5, 129.4, 129.2,
129.1, 128.3, 128.1, 128.0, 127.1, 126.7, 77.4, 77.1, 76.7, 73.4, 58.0,
56.0, 55.7, 53.0, 51.6, 34.2, 30.8 ppm; νmax(neat)/cm−1: 2981, 1733,
1245, 1141, 1031, 697 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C27H2735ClNO2 432.1730; found 432.1726; calcd for
C27H2737ClNO2 434.1701; found 434.1696.
26
(211 mg, 80%). [α]D = +65.0 (c 1.0, CHCl3); Mp 170−172 °C;
1H NMR (400 MHz, CDCl3): δ 7.80−7.74 (m, 2 H), 7.41−7.28
(m, 7 H), 4.78−4.71 (m, 1 H), 4.33−4.17 (m, 3 H), 4.00−3.94 (m,
1 H), 2.77−2.71 (m, 1 H), 2.44 (s, 3 H), 2.10−2.02 (m, 1 H),
1.65−1.42 (m, 3 H), 1.34−1.02 (m, 15 H), 0.88 (t, J = 5.2 Hz, 1
H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 144.9, 135.4,
134.3, 130.0, 129.2, 128.6, 127.6, 77.3, 77.1, 76.8, 76.2, 73.8, 55.7,
54.3, 53.6, 31.9, 31.0, 29.9, 29.6, 29.4, 26.5, 22.7, 21.7, 14.2 ppm;
νmax(neat)/cm−1: 2981, 1733, 1456, 1232, 940, 816, 698, 551 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C30H42O5NS 528.2778; found
528.2768.
(4S,6R,8R,9aS)-8-Bromo-6-phenethyl-4-phenylhexahydropyrido-
[2,1-c][1,4]oxazin-1(6H)-one (13a, Table 4, Entry 6). Following the
general procedure C, the title compound 13a was prepared from
compound 8a (109 mg) and phenyl propionaldehyde as a white
(4S,6R,8R,9aS)-1-Oxo-4-phenyl-6-undecyloctahydropyrido[2,1-
c][1,4]oxazin-8-yl 4-methylbenzenesulfonate (15b, Table 4, Entry
12). Following the general procedure C, the title compound 15b was
prepared from compound 8a (109 mg) and dodecanal as a white
26
solid (186 mg, 90%). [α]D = +225.0 (c 1.0, CHCl3); Mp 192−194
1
°C; H NMR (400 MHz, CDCl3): δ 7.40−7.14 (m, 8 H), 7.11−
7.05 (m, 2 H), 4.40−4.24 (m, 4 H), 4.11 (dd, J = 3.2, 9.2 Hz, 1 H),
2.82−2.70 (m, 2 H), 2.51−2.27 (m, 3 H), 2.20−1.80 (m, 3H),
1.63−1.54 (m, 1 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ
168.9, 141.4, 135.3, 129.3, 128.6, 128.5, 128.2, 126.1, 77.3, 77.1,
76.8, 73.9, 56.3, 55.8, 54.7, 44.7, 35.0, 34.7, 33.0, 32.6 ppm;
νmax(neat)/cm−1: 2981, 1726, 1453, 1242, 1133, 698 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C22H2579BrNO2 414.1063; found
414.1063; calcd for C22H2581BrNO2 416.1043; found 416.1042.
( 4 S , 6 S , 8 R , 9 a S ) - 6 - B e n z h y d r y l - 8 - b r o m o - 4 -
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (13b, Table
4, Entry 7). Following the general procedure C, the title compound
13b was prepared from compound 8a (109 mg) and diphenyl
26
solid (216 mg, 78%). [α]D = +223.0 (c 1.0, CHCl3); Mp 178−180
1
°C; H NMR (400 MHz, CDCl3): δ 7.80−7.74 (m, 2 H), 7.41−
7.28 (m, 7 H), 4.78−4.68 (m, 1 H), 4.33−4.17 (m, 3 H), 4.00−3.93
(m, 1 H), 2.77−2.70 (m, 1 H), 2.44 (s, 3 H), 2.10−2.01 (m, 1 H),
1.65−1.43 (m, 3 H), 1.34−1.02 (m, 20 H), 0.88 (t, J = 5.2 Hz, 1
H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 168.2, 143.9, 134.4,
133.3, 129.0, 128.2, 127.5, 126.6, 76.3, 76.0, 75.8, 75.2, 72.8, 54.7,
53.3, 52.6, 30.9, 30.0, 28.9, 28.6, 28.4, 25.5, 21.7, 20.7, 13.1 ppm;
νmax(neat)/cm−1: 2981, 1734, 1456, 1190, 1037, 751, 698 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C32H46O5 NS 556.3091; found
556.3081.
26
N-((4S,6R,8R,9aS)-6-Nonyl-1-oxo-4-phenyloctahydropyrido[2,1-
c][1,4]oxazin-8-yl) Acetamide (16a, Table 4, Entry 13). Following
the general procedure E, the title compound 16a was prepared from
compound 8a (109 mg) and decanal as a semisolid (155 mg, 75%).
acetaldehyde as a white solid (211 mg, 80%). [α]D = +183.0 (c
1.0, CHCl3); Mp 201−203 °C; 1H NMR (400 MHz, CDCl3): δ
7.51−7.30 (m, 4 H), 7.28−7.13 (m, 6 H), 7.09−7.00 (m, 3 H),
6.98−6.90 (m, 2 H), 4.44−4.31 (m, 3 H), 4.13−3.97 (m, 3 H),
3.38−3.32 (m, 1 H), 2.61−2.43 (m, 2 H), 1.93−1.84 (m, 2 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 168.7, 142.0, 140.9,
134.5, 129.9, 129.4, 129.2, 129.1, 128.3, 128.1, 128.0, 127.1, 126.7,
77.3, 77.1, 76.8, 76.5, 73.3, 58.6, 56.4, 56.0, 51.3, 44.0, 34.9, 31.7
ppm; νmax(neat)/cm−1: 2933, 1738, 1454, 1228, 1021, 702 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C27H2779BrNO2 476.1220; found
476.1216; calcd for C27H2781BrNO2 478.1200; found 478.1195.
(4S,6R,8R,9aS)-8-Hydroxy-4-phenyl-6-propylhexahydropyrido-
[2,1-c][1,4]oxazin-1(6H)-one (14a, Table 4, Entry 8). Following the
general procedure, D, the title compound 14a was prepared from
compound 8a (109 mg) and butanal as a colorless liquid (127 mg,
26
1
[α]D = +74.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ
7.39−7.30 (m, 5 H), 5.94 (bs, 1 H), 4.27−4.08 (m, 5 H), 2.72−
2.63 (m, 1 H), 2.21−2.19 (m, 1H), 1.95 (s, 3 H), 1.62−1.49 (m, 2
H), 1.44−1.02 (m, 17 H), 0.87 (t, J = 6.8 Hz, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.8, 169.4, 137.0, 129.1, 128.7,
128.1, 77.4, 77.1, 76.7, 73.0, 57.6, 54.4, 54.1, 42.6, 31.9, 31.7, 31.0,
29.6, 29.3, 26.1, 23.6, 22.7, 14.2 ppm; νmax(neat)/cm−1: 2980, 1739,
1549, 1233, 1021, 702 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C25H39O3N2 415.2955; found 415.2952.
N-((4S,6R,8R,9aS)-1-Oxo-4-phenyl-6-undecyloctahydropyrido-
[2,1-c][1,4]oxazin-8-yl) Acetamide (16b, Table 4, Entry 141).
Following the general procedure E, the title compound 16b was
prepared from compound 8a (109 mg) and dodecanal as a semisolid
26
88%). [α]D = +65.0 (c 1.0, CHCl3); 1H NMR (400 MHz,
26
(159 mg, 72%). [α]D = +94.0 (c 1.0, CHCl3); 1H NMR (400
CDCl3): δ 7.38−7.30 (m, 5 H), 4.35−4.22 (m, 3 H), 4.02−3.95 (m,
2 H), 2.83−2.75 (m, 1 H), 2.46 (bs, 1 H), 2.16−1.96 (m, 2H),
1.54−1.35 (m, 4 H), 1.22−1.09 (m, 2 H), 0.77 (t, J = 5.6 Hz, 1 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 135.7, 128.2,
127.9, 127.6, 76.5, 76.3, 76.0, 72.6, 63.6, 55.5, 53.6, 52.9, 33.2, 32.1,
31.9, 18.8, 13.2 ppm; νmax(neat)/cm−1: 2955, 2870, 1732, 1456,
1330, 1228, 1138, 761, 647 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C17 H24 O3 N 290.1751; found 290.1750. Compound 14a was also
prepared using the same method starting from 8a (109 mg) and
butanal diethyl acetal (73 mg) in 170 mg, 76% yield (Table 4 Entry
10). All data were in agreement with those presented above.
(4S,6R,8R,9aS)-8-Hydroxy-4-phenyl-6-undecylhexahydropyrido-
[2,1-c][1,4]oxazin-1(6H)-one (14b, Table 4, Entry 9). Following the
general procedure D, the title compound 14b was prepared from
compound 8a (109 mg) and dodecanal as a colorless liquid (172
MHz, CDCl3): δ 7.41−7.30 (m, 5 H), 5.94 (bs, 1 H), 4.27−4.08
(m, 5 H), 2.72−2.63 (m, 1 H), 2.21−2.14 (m, 1H), 1.95 (s, 3 H),
1.47−1.02 (m, 20 H), 0.87 (t, J = 6.8 Hz, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.8, 169.3, 137.0, 129.0, 128.7,
128.1, 77.4, 77.1, 76.7, 72.9, 57.7, 54.4, 54.1, 42.6, 31.9, 31.8, 31.1,
29.7, 29.6, 29.4, 26.0, 23.6, 22.7, 14.2 ppm; νmax(neat)/cm−1: 2971,
1742, 1381, 1152, 958, 600 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C27H43O3N2 443.3268; found 443.3264.
(4S,6R,7S,8S,9aS)-8-Chloro-7-methyl-6-phenethyl-4-
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (17a, Table 5,
Entry 1). Following the general procedure C, the title compound
16a was prepared from compound 8c (116 mg) and 3-phenyl-
26
propionaldehyde as a white solid (176 mg, 92%). [α]D = +64.0 (c
1.0, CHCl3); Mp 128−130 °C; 1H NMR (400 MHz, CDCl3): δ
7.39−7.31 (m, 5 H), 7.28−7.25 (m, 2 H), 7.21−7.16 (m, 1 H),
7.14−7.10 (m, 2 H), 4.44−4.34 (m, 2 H), 4.27 (dd, J = 2.4, 6.0 Hz,
1 H), 4.15 (dd, J = 2.4, 6.0 Hz, 1 H), 3.96 (dt, J = 4.4, 4.8 Hz, 1
26
1
mg, 90%). [α]D = +187.0 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3): δ 7.40−7.30 (m, 5 H), 4.35−4.21 (m, 3 H), 4.02−3.96 (m,
2 H), 2.83−2.76 (m, 1 H), 2.19−1.96 (m, 2H), 1.54−1.45 (m, 2
2085
https://dx.doi.org/10.1021/acs.joc.0c01897
J. Org. Chem. 2021, 86, 2076−2089

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
H), 2.94−2.88 (m, 1 H), 2.70−2.65 (m, 1 H), 2.45−2.28 (m, 3 H),
1.98−1.92 (m, 1 H), 1.67−1.59 (m, 1 H), 0.86(d, J = 5.2 Hz, 3 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.1, 141.9, 135.2,
129.3, 129.2, 128.8, 128.6, 128.3, 126.1, 77.4, 77.1, 76.7, 73.9, 61.2,
59.3, 55.5, 55.3, 36.0, 35.0, 33.1, 26.6, 15.7 ppm; νmax(neat)/cm−1:
2980, 1604, 1452, 1042, 909, 595 cm−1; HRMS (ESI) m/z: [M]+
calcd for C23H2735ClNO2 384.1730; found 384.1734; calcd for
C23H2737ClNO2 386.1701; found 386.1709.
cm−1; HRMS (ESI) m/z: [M]+ calcd for C24H30NO3 380.2225;
found 380.2221.
(4S,6R,7S,8aS)-7-(2-Hydroxypropan-2-yl)-4-phenyl-6-propylhex-
ahydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (18c, Table 5, Entry 3).
Following the general procedure A, the title compound 17c was
prepared from compound 8e (123 mg) and butanal as a white solid
26
(114 mg, 72%). [α]D = +182.0 (c 1.0, CHCl3); Mp 140−142 °C;
1H NMR (400 MHz, CDCl3): δ 7.49−7.28 (m, 5 H), 4.29−4.15
(m, 2 H), 4.07−4.02 (m, 2 H), 2.96 (q, J = 5.2 Hz, 1 H), 2.40−
2.25 (m, 2 H), 1.87−1.81 (m, 1 H), 1.41 (bs, 1 H), 1.33−1.06 (m,
10 H), 0.54 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 172.8, 138.5, 128.6, 128.5, 128.3, 77.4, 77.1, 76.7, 72.4,
71.1, 65.9, 60.7, 60.5, 53.3, 38.5, 30.1, 29.5, 29.0, 18.3, 13.9 ppm;
νmax(neat)/cm−1: 2981, 1733, 1355, 1111, 1017, 698 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C19H28NO3 318.2069; found 318.2079.
(4S,6R,7R,8aS)-6-Phenethyl-4-phenyl-7-(prop-1-en-2-yl) hexahy-
dro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (18d, Table 5, Entry 4).
Following the general procedure E, the title compound 17d was
prepared from compound 8e (123 mg) and phenyl propionaldehyde
in the presence of catalytic amount of Sc(OTf)3 as a white solid (90
(4S,6R,7S,8S,9aS)-8-Bromo-7-methyl-6-phenethyl-4-
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (17b, Table
5, Entry 1). Following the general procedure C, the title compound
16b was prepared from compound 8c (116 mg) and 3-phenyl-
26
propionaldehyde as a white solid (194 mg, 91%). [α]D = +183.0 (c
1.0, CHCl3); Mp 136−138 °C; 1H NMR (400 MHz, CDCl3): δ
7.41−7.26 (m, 7 H), 7.21−7.16 (m, 1 H), 7.13−7.08 (m, 2 H),
4.51−4.35 (m, 2 H), 4.27 (dd, J = 3.6, 7.2 Hz, 1 H), 4.19−4.10 (m,
2 H), 2.96−2.84 (m, 1 H), 2.70−2.50 (m, 2 H), 2.35−2.26 (m, 1
H), 2.11−2.01 (m, 1 H), 1.71−1.58 (m, 2 H), 0.87 (d, J = 6.8 Hz,
3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 168.8, 141.9,
135.1, 129.3, 128.8, 128.6, 128.3, 126.1, 77.4, 77.1, 76.7, 73.9, 59.4,
55.9, 55.5, 54.3, 36.3, 36.2, 33.0, 26.4, 17.6 ppm; νmax(neat)/cm−1:
2981, 1739, 1235, 1064, 766, 635, 528 cm−1; HRMS (ESI) m/z:
[M]+ calcd for C23H2779BrNO2 428.1225; found 428.1221; calcd for
C23H2781BrNO2 430.1205; found 430.1201.
26
1
mg, 51%). [α]D = −63.0 (c 1.0, CHCl3); Mp 168−170 °C; H
NMR (400 MHz, CDCl3): δ 7.51−7.32 (m, 5 H), 7.16−7.04 (m, 3
H), 6.58−6.53 (m, 2 H), 4.87−4.82 (m, 2 H), 4.28−4.16 (m, 3 H),
3.91−3.84 (m, 1 H), 2.83−2.70 (m, 2 H), 2.44−2.32 (m, 3 H),
1.73−1.62 (m, 2 H), 1.55 (s, 3 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 173.4, 144.2, 142.3, 139.3, 128.9, 128.3, 128.1, 128.1,
127.8, 125.5, 113.1, 77.4, 77.1, 76.7, 71.2, 68.1, 63.1, 58.5, 49.8,
33.4, 31.0, 29.8, 19.2. ppm; νmax(neat)/cm−1: 2981, 1756, 1454,
1137, 1071, 699 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C24H28NO2 362.2120; found 362.2122.
(4S,6R,7S,8S,9aS)-8-Hydroxy-7-methyl-6-phenethyl-4-
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (17c, Table 5,
Entry 1). Following the general procedure C, the title compound
16c was prepared from compound 8c (116 mg) and phenyl
26
propionaldehyde as a white solid (151 mg, 83%). [α]D = +82.0 (c
1.0, CHCl3); Mp 132−134 °C; 1H NMR (400 MHz, CDCl3): δ
7.39−7.31 (m, 5 H), 7.28−7.25 (m, 2 H), 7.19−7.16 (m, 1 H),
7.14−7.08 (m, 2 H), 4.44−4.34 (m, 2 H), 4.27 (dd, J = 2.8, 5.6 Hz,
1 H), 4.13 (dd, J = 2.8, 5.6 Hz, 1 H), 3.65 (dt, J = 4.0, 4.4 Hz, 1
H), 2.94−2.87 (m, 1 H), 2.67−2.60 (m, 1 H), 2.34−2.27 (m, 1 H),
2.20−2.15 (m, 1 H), 2.06−1.98 (m, 1 H), 1.76−1.66 (m, 1 H),
1.62−1.57 (m, 1 H), 0.81(d, J = 5.6 Hz, 3 H), ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 170.4, 142.3, 135.7, 129.2, 129.0, 128.7,
128.5, 128.3, 125.9, 77.3, 77.1, 76.8, 73.9, 70.01 59.0, 55.6, 54.6,
34.9, 33.3, 33.1, 27.4, 13.9 ppm; νmax(neat)/cm−1: 2981, 1701, 1245,
1059, 699 cm−1; HRMS (ESI) m/z: [M]+ calcd for C23H28NO3
366.2069; found 366.2072.
(4S,6R,8R,9aS)-8-Chloro-8-methyl-6-phenethyl-4-
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (19a, Table 5,
Entry 5). Following the general procedure C, the title compound
18a was prepared from compound 8d (116 mg) and 3-phenyl-
26
propionaldehyde as a white solid (145 mg, 76%). [α]D = +162.0 (c
1.0, CHCl3); Mp 138−140 °C; 1H NMR (400 MHz, CDCl3): δ
7.49−7.42 (m, 2 H), 7.40−7.24 (m, 5 H), 7.22−7.15 (m, 1 H),
7.14−7.08 (m, 2 H), 4.75−4.55 (m, 2 H), 4.40 (t, J = 4.4 Hz, 1 H),
3.76 (t, J = 5.6 Hz, 1 H), 3.30−3.23 (m, 1 H), 2.88−2.80 (m, 1 H),
2.66 (t, J = 8.8 Hz, 1 H), 2.17−2.11 (m, 1 H), 1.98−1.71 (m, 3 H),
1.70 (s, 3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 170.1,
141.7, 137.3, 129.1, 128.6, 128.5, 128.3, 127.9, 126.2, 67.6, 67.4,
54.9, 53.5, 52.9, 43.4, 38.9, 35.2, 33.0, 31.6 ppm; νmax(neat)/cm−1:
2971, 1740, 1382, 1151, 953, 700 cm−1; HRMS (ESI) m/z: [M]+
calcd for C23H2735ClNO2 384.1730; found 384.1734; calcd for
C23H2737ClNO2 386.1701; found 386.1709.
(4S,6R,7S,8aS)-7-(2-Chloropropan-2-yl)-6-phenethyl-4-phenyl-
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (18a, Table 5,
Entry 2). Following the general procedure C, the title compound
17a was prepared from compound 8e (123 mg) and phenyl
26
propionaldehyde as a white solid (125 mg, 63%). [α]D = +32.0 (c
( 4 S , 6 R , 8 R , 9 a S ) - 8 - C h l o r o - 8 - m e t h y l - 4 - p h e n y l - 6 -
propylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (19b, Table 5,
Entry 6). Following the general procedure C, the title compound
18b was prepared from compound 8d (116 mg) and butanal as a
1.0, CHCl3); Mp 152−154 °C; 1H NMR (400 MHz, CDCl3): δ
7.49−7.32 (m, 5 H), 7.21−7.08 (m, 3 H), 6.86−6.81 (m, 2 H),
4.40−4.33 (m, 1 H), 4.28−4.160 (m, 4 H), 3.10−3.04 (m, 1 H),
2.60 (q, J = 4.8, 8 Hz, 1 H), 2.44−2.37 (m, 3 H), 2.23−2.11 (m, 3
H), 1.73−1.64 (m, 1 H), 1.57 (s, 3 H), 1.48 (s, 3 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 171.2, 142.3, 137.4, 129.1, 128.8,
128.4, 128.3, 128.2, 125.7, 77.4, 77.1, 76.7, 72.9, 72.3, 66.2, 60.6,
59.6, 56.5, 39.0, 32.8, 32.5, 32.1, 32.0 ppm; νmax(neat)/cm−1: 2981,
1752, 1384, 1156, 698 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C24H2935ClNO2 398.1886; found 398.1884; calcd for
C24H2937ClNO2 400.1857; found 400.1861.
26
white solid (115 mg, 72%). [α]D = +126.0 (c 1.0, CHCl3); Mp
1
126−128 °C; H NMR (400 MHz, CDCl3): δ 7.49−7.42 (m, 2 H),
7.40−7.27 (m, 3 H), 4.80 (dd, J = 4.4, 7.6 Hz, 1 H), 4.62 (dd, J =
4.8, 7.7 Hz, 1 H), 4.39 (t, J = 4.4 Hz, 1 H), 3.72 (t, J = 5.6 Hz, 1
H), 3.23−3.13 (m, 1 H), 2.88−2.79 (m, 1 H), 2.10−2.03 (m, 1 H),
1.87 (dd, J = 6.0 Hz, 1 H), 1.67 (s, 3 H), 1.65−1.59 (m, 2 H),
1.48−1.36 (m, 3 H), 0.87 (t, J = 7.2 Hz, 1 H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 170.2, 137.6, 129.0, 128.3, 127.8, 77.4, 77.1,
76.7, 67.7, 67.6, 54.8, 53.5, 52.9, 43.5, 38.9, 35.4, 33.0, 18.4, 14.4
ppm; νmax(neat)/cm−1: 2965, 1723, 1367, 1148, 948, 688 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C18H2535ClNO2 322.1573; found
322.1572; calcd for C18H2537ClNO2 324.1544; found 324.1551.
(4S,6R,8R,9aS)-8-Hydroxy-8-methyl-6-phenethyl-4-
phenylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (19c, Table 5,
Entry 7). Following the general procedure A, the title compound
18c was prepared from compound 8d (116 mg) and phenyl
(4S,6R,7S,8aS)-7-(2-Hydroxypropan-2-yl)-6-phenethyl-4-phenyl-
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (18b, Table 5,
Entry 2). Following the general procedure A, the title compound
17b was prepared from compound 8e (123 mg) and 3-phenyl-
26
propionaldehyde as a white solid (144 mg, 76%). [α]D = +136.0 (c
1.0, CHCl3); Mp 134−136 °C; 1H NMR (400 MHz, CDCl3): δ
7.49−7.34 (m, 5 H), 7.21−7.08 (m, 3 H), 6.77−6.69 (m, 2 H),
4.35−4.12 (m, 3 H), 4.06 (dd, J = 4.0, 7.6 Hz, 1 H), 3.06 (q, J =
5.2 Hz, 1 H), 2.52−2.25 (m, 2 H), 2.01−1.94 (m, 1 H), 1.71−1.44
(m, 3 H), 1.28 (s, 3 H), 1.14 (s, 3 H) ppm; 13C{1H} NMR (100
MHz, CDCl3): δ 173.1, 142.5, 138.8, 128.8, 128.4, 128.2, 125.6
77.42, 77.1, 76.8, 72.1, 71.2, 66.6, 61.4, 60.2, 52.7, 37.8, 31.2, 29.4,
28.9 ppm; νmax(neat)/cm−1: 2980, 1667, 1453, 1155, 1029, 646
26
propionaldehyde as a white solid (146 mg, 80%). [α]D = +56.0 (c
1.0, CHCl3); Mp 136−134 °C; 1H NMR (400 MHz, CDCl3): δ
7.46−7.29 (m, 5 H), 7.19−7.07 (m, 3 H), 6.79−6.74 (m, 2 H), 4.52
(q, J = 10.8 Hz, 1 H), 4.29−4.20 (m, 2 H), 3.99 (dd, J = 2.4, 4.0
Hz, 1 H), 3.25 (bs, 1 H), 3.12−3.05 (m, 1 H), 2.51−2.40 (m, 2 H),
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1.94−1.47 (m, 3 H), 1.32 (s, 3 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 175.1, 142.1, 139.4, 129.0, 128.3, 128.2, 128.1, 127.1,
125.8, 77.4, 77.1, 76.7, 69.6, 66.5, 60.1, 55.3, 53.8, 43.2, 36.3, 35.6,
31.3, 30.5 ppm; νmax(neat)/cm−1: 2981, 1732, 1391, 1115, 751, 697
cm−1; HRMS (ESI) m/z: [M]+ calcd for C23H28NO3 366.2069;
found 366.2071.
was removed by filtration, and the filtrate was concentrated. The
resulting crude compound was washed with diethyl ether twice for
removal of nonpolar impurities and dried to give pure semisolid.
(2R,4R,6S)-4-Hydroxy-6-propylpiperidine-2-carboxylic Acid (21a,
Table 6 Entry 1): (Starting Material is 9b, Table 2, Entry 3).
Following the general procedure F, the title compound was prepared
26
from compound 9b (183 mg) as a white solid (88 mg, 95%). [α]D
( 4 S , 6 R , 8 R , 9 a S ) - 8 - H y d r o x y- 8 - m e t h y l - 4 - p h e n y l - 6 -
propylhexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (19d, Table 5,
Entry 8). Following the general procedure A, the title compound
18d was prepared from compound 8d (116 mg) and butanal as a
+40.0 (c 1.0, MeOH); Mp 260−262 °C; 1H NMR (400 MHz,
D2O): δ 4.18−4.10 (m, 1 H), 3.88−3.72 (m, 2 H), 2.28−2.16 (m, 1
H), 2.04−1.72 (m, 3 H), 1.71−1.56 (m, 2 H), 1.50−1.20 (m, 2 H),
0.91 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
δ 176.6, 64.7, 56.0, 53.1, 36.0, 35.6, 35.2, 21.0, 15.6 ppm;
νmax(neat)/cm−1: 2971, 2489, 1596, 1393, 1096, 836, 576 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C9H18NO3 188.1286; found
188.1290.
26
white solid (114 mg, 75%). [α]D = +320.0 (c 1.0, CHCl3); Mp
1
128−130 °C; H NMR (400 MHz, CDCl3): δ 7.46−7.25 (m, 4 H),
7.31−7.26 (m, 1 H), 4.60−4.51 (m, 1 H), 4.33−4.20 (m, 2 H),
3.95−3.90 (m, 1 H), 3.24 (m, 1 H), 2.96−2.90 (m, 1 H), 2.462.38
(m, 1 H), 1.881.70 (m, 2 H), 1.50−1.36 (m, 2 H), 1.28 (s, 3 H),
1.22−1.12 (m, 2 H), 1.32 (t, J = 6.8 Hz, 3 H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 175.2, 139.7, 128.8, 127.9, 127.0, 77.4, 77.1,
76.8, 69.6, 66.5, 59.9, 55.4, 53.7, 43.3, 36.3, 35.8, 31.3, 17.7, 14.2
ppm; νmax(neat)/cm−1: 2956, 2872, 1717, 1399, 1123, 754 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C18H26NO3 304.1912; found
304.1917.
(2S,4S,6R)-4-Hydroxy-6-propylpiperidine-2-carboxylic Acid
(21a', Table 6 Entry 1): (Starting Material is 9b′, Table 2, Entry
8). Following the general procedure F, the title compound was
prepared from compound 9b′ (183 mg) as a white solid (83 mg,
26
1
93%). [α]D = −64.0 (c 1.0, MeOH); Mp 280−282 °C; H NMR
(400 MHz, D2O): δ 4.06−3.98 (m, 1 H), 3.75−3.68 (m, 2 H),
2.17−2.06 (m, 1 H), 1.90−1.63 (m, 3 H), 1.60−1.46 (m, 2 H),
1.35−1.21 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm; 13C{1H} NMR
(100 MHz, CDCl3): δ 173.8, 61.9, 53.2, 50.2, 33.2, 32.8, 32.4, 18.2,
12.8 ppm; νmax(neat)/cm−1: 2971, 1616, 1381, 1085, 940, 586 cm−1;
HRMS (ESI) m/z: [M]+ calcd for C9H18NO3 188.1286; found
188.1290.
(4S,6R,9aS)-8-Chloro-6-phenethyl-4-phenyl-3,4,9,9a-
tetrahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (20a, Table 5, Entry
9). Following the general procedure C, the title compound 19a was
prepared from compound 8b (107 mg) and 3-phenylpropionalde-
26
hyde as a semisolid (128 mg, 70%). [α]D = −83.0 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): δ 7.37−7.29 (m, 5 H), 7.23−7.11
(m, 3 H), 7.04−6.98 (m, 2 H), 5.77−5.73 (m, 1 H), 4.37−4.22 (m,
3 H), 4.11 (dd, J = 5.2 Hz, 1 H), 3.13−3.05 (m, 1 H), 2.90−2.79
(m, 1 H), 2.72−2.41 (m, 3 H), 1.78−1.62 (m, 1 H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ 169.2, 141.4, 135.9, 129.2, 129.0,
128.5, 128.5, 128.2, 127.5, 126.0, 125.6, 77.4, 77.1, 76.7, 73.4, 57.2,
56.0, 53.8, 35.9, 32.4, 30.1 ppm; νmax(neat)/cm−1: 2958,1746, 1454,
1121, 1040, 747, 660 cm−1; HRMS (ESI) m/z: [M]+ calcd for
C22H2335ClNO2 368.1417; found 368.1418; calcd for
C22H2337ClNO2 370.1388; found 370.1397.
(2R,4R,6S)-6-Heptyl-4-hydroxypiperidine-2-carboxylic Acid (21b,
Table 6 Entry 2). Following the general procedure F, the title
compound 20b was prepared from compound 9e (211 mg) as a
26
white solid (110 mg, 92%). [α]D = −63.0 (c 1.0, CHCl3); Mp
1
164−166 °C; H NMR (400 MHz, D2O): δ 4.10−4.03 (m, 1 H),
3.98 (t, J = 4.4 Hz, 1 H), 3.72−3.64 (m, 1 H), 2.09 (t, J = 4.0 Hz, 3
H), 1.83−1.65 (m, 2 H), 1.58−1.50 (m, 2 H), 1.34−1.15 (m, 10
H), 0.72 (t, J = 5.6 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 172.5, 61.7, 52.1, 49.7, 33.5, 31.8, 31.2, 31.1, 28.2, 24.4,
22.1, 13.5 ppm; νmax(neat)/cm−1: 2971, 1740, 1382, 1151, 953, 700
cm−1; HRMS (ESI) m/z: [M]+ calcd for C13H26NO3 244.1913;
found 244.1912.
(4S,6R,9aS)-8-Bromo-6-phenethyl-4-phenyl-3,4,9,9a-
tetrahydropyrido[2,1-c][1,4]oxazin-1(6H)-one (20b, Table 5, Entry
9). Following the general procedure C, the title compound 19b was
prepared from compound 8b (107 mg) and 3-phenylpropionalde-
(2R,4R,6S)-4-Acetamido-6-phenethylpiperidine-2-carboxylic
Acid (21c, Table 6, Entry 3). Following the general procedure F, the
title compound was prepared from compound 10a (234 mg) as a
26
hyde as a semisolid (146 mg, 71%). [α]D = −232.0 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.37−7.29 (m, 5 H),
7.23−7.11 (m, 3 H), 7.04−6.98 (m, 2 H), 6.01−5.92 (m, 1 H),
4.37−4.26 (m, 3 H), 4.11 (dd, J = 5.2 Hz, 1 H), 3.05−2.91 (m, 2
H), 2.74−2.66 (m, 2 H), 2.47−2.40 (m, 1 H), 1.78−1.64 (m, 2 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 141.4, 135.9,
129.2, 129.1, 128.5, 128.5, 128.2, 127.5, 126.0, 125.6, 77.4, 77.1,
76.7, 73.4, 57.1, 56.0, 53.8, 35.9, 32.4, 30.1 ppm; νmax(neat)/cm−1:
2981, 1727, 1454, 1249, 1137, 700, 594 cm−1; HRMS (ESI) m/z:
[M]+ calcd for C22H2379BrNO2 412.0912; found 414.0907; calcd for
C22H2381BrNO2 414.0892; found 414.0918.
26
white solid (133 mg, 91%). [α]D = −80.0 (c 1.0, H2O); Mp 182−
1
184 °C; H NMR (400 MHz, D2O): δ 7.45−7.21 (m, 5 H), 4.16−
3.97 (m, 2 H), 3.78−3.60 (m, 1 H), 2.88−2.67 (m, 2 H), 2.39−2.24
(m, 1 H), 2.34−2.02 (m, 4 H), 1.92 (s, 3 H), 1.78−1.71 (m, 1 H)
ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 140.6, 129.0,
128.6, 126.7, 51.4, 41.3, 31.1, 30.9, 30.4, 30.1, 22.0 ppm;
νmax(neat)/cm−1: 2980, 1587, 1379, 1085, 586 cm−1; HRMS
(ESI) m/z: [M]+ calcd for C16H23N2O3 291.1708; found 291.1711.
(2S,4S,6R)-4-Acetamido-6-phenethylpiperidine-2-carboxylic
Acid (21c′, Table 6 Entry 3). Following the general procedure F, the
title compound was prepared from compound 10a′ (234 mg) as a
General Procedure F: Hydrogenation Reaction. The
compound (0.5 mmol) was dissolved in ethanol (10 mL) and
exhaustively (14 h) hydrogenated with a double pressured balloon
over 10% Pd−C (0.1 g). The catalyst was removed by filtration, and
the filtrate was concentrated. The resulting crude compound was
washed with ether twice for removal of nonpolar impurities and
dried to give pure white solid.
General Procedure G: Hydrogenation Reaction. The
compound (0.5 mmol) was dissolved in ethanol (10 mL) containing
TFA (1 equiv) at room temperature and exhaustively (14 h)
hydrogenated with a double pressured balloon over 10% Pd(OH)2
(0.1 g). The catalyst was removed by filtration, and the filtrate was
concentrated. The resulting crude compound was washed with ether
twice for removal of nonpolar impurities and dried to give pure
white solid.
26
white solid (121 mg, 89%). [α]D = +40.00 (c 1.0, MeOH); Mp
1
170−172 °C; H NMR (400 MHz, D2O): δ 7.32−7.03 (m, 5 H),
4.00−3.89 (m, 1 H), 3.78−3.69 (m, 1 H), 3.60−3.52 (m, 1 H),
2.73−2.54 (m, 2 H), 2.22−2.17 (m, 1 H), 2.06−1.87 (m, 3 H), 1.81
(s, 3 H), 1.71−1.60 (m, 2 H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 173.6, 173.3, 140.6, 128.9, 128.5, 126.6, 53.6, 51.4, 41.3,
31.1, 30.9, 30.5, 30.0, 22.0 ppm; νmax(neat)/cm−1: 2981, 1627, 1371,
749, 516 cm−1; HRMS (ESI) m/z: [M]+ calcd for C16H23N2O3
291.1708; found 291.1711.
(2S,4R,6R)-4-Hydroxy-6-propylpiperidine-2-carboxylic Acid
(21d, Table 6, Entry 4). Following the general procedure G, the
title compound 20d was prepared from compound 14a (145 mg) as
26
a white solid (73 mg, 76%). [α]D = −116.0 (c 1.0, CHCl3); Mp
1
General Procedure H: Hydrogenation Reaction. The
compound (0.5 mmol) was dissolved in ethanolic HCl (10 mL)
at room temperature and exhaustively (14 h) hydrogenated with a
double pressured balloon over 10% Pd(OH)2 (0.1 g). The catalyst
246−248 °C; H NMR (400 MHz, D2O): δ 4.28−3.98 (m, 2 H),
3.75−3.68 (m, 1 H), 2.38−2.15 (m, 1 H), 2.13−2.00 (m, 1 H),
1.92−1.79 (m, 1 H), 1.70−1.46 (m, 3 H), 1.35−1.28 (m, 2 H), 0.81
(t, J = 6.0 Hz, 3 H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 13C
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170.5, 61.5, 53.4, 51.3, 48.9, 33.5, 31.0, 17.8, 12.7 ppm; νmax(neat)/
cm−1: 2973, 1656, 1451, 1032, 956, 593 cm−1; HRMS (ESI) m/z:
[M]+ calcd for C9H18NO3 188.1286; found 188.1290.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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and NMR spectra (PDF)
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CCDC 1950070, 1950084, and 2014403−2014404 contain
the supplementary crystallographic data for this paper. These
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AUTHOR INFORMATION
Corresponding Author
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0000-0002-7241-7118; Email: A.Dobbs@gre.ac.uk
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Authors
Ramana Reddy Mittapalli − School of Science, University of
Greenwich, Kent ME4 4TB, United Kingdom; orcid.org/
0000-0003-2858-3829
Simon J. Coles − UK National Crystallography Service,
University of Southampton, Southampton SO17 1BJ, United
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Wim T. Klooster − UK National Crystallography Service,
University of Southampton, Southampton SO17 1BJ, United
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01897
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank that European Union (Grant
706581 - MESO-JBIR-102; Marie Curie Individual Fellow-
ship to R.R.M.). The EPSRC National Mass Spectrometry
Service and the University of Greenwich (Dr. Iain Goodall)
are gratefully acknowledged for running high resolution mass
spectra. The UK National Crystallography Service39 is
gratefully acknowledged for obtaining and determining all
X-ray structures.
2088
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https://dx.doi.org/10.1021/acs.joc.0c01897
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